Review article
Genetics of non-alcoholic fatty liver disease and associated metabolic disorders
Genética de la enfermedad del hígado graso no alcohólica y trastornos metabólicos asociados
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"nombre" => "Ruben" "apellidos" => "Hernaez" "email" => array:1 [ 0 => "rhernaez@jhsph.edu" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Medicine, Johns Hopkins School of Medicine, Baltimore, USA" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Medicine, Georgetown University Hospital/Washington Hospital Center, Washington, District of Columbia, USA" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Genética de la enfermedad del hígado graso no alcohólica y trastornos metabólicos asociados" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Brief epidemiology and genetic basis of non-alcoholic fatty liver disease</span><p id="par0005" class="elsevierStylePara elsevierViewall">Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> represents a wide spectrum of diseases characterized by the presence hepatic steatosis in the absence of significant alcohol consumption or other causes of liver disease.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> The pathogenic processes leading to steatosis, steatohepatitis (NASH) and fibrosis are multifactorial and involve both environmental and genetic factors.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Obesity and type 2 diabetes mellitus (T2DM)/insulin resistance are the most common risk factors for the development and progression of NAFLD.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> A recent meta-analysis showed a direct association between waist circumference and NAFLD (odds ratio (OR)<span class="elsevierStyleHsp" style=""></span>∼<span class="elsevierStyleHsp" style=""></span>1.10–1.13 per 1<span class="elsevierStyleHsp" style=""></span>cm increase in waist circumference) and between intra-abdominal fat and NAFLD (OR<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.50 per 1<span class="elsevierStyleHsp" style=""></span>mm increase in visceral fat thickness).<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In addition, between 47% and 71% of NAFLD patients have metabolic syndrome,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and conversely, the presence of metabolic syndrome is a strong predictor for NAFLD.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Consequently, NAFLD is considered the hepatic component of the metabolic syndrome.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> As expected, patients with T2DM have shown a prevalence of NAFLD ranging from 40% to 80%,<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a> and the presence of T2DM is associated with more severe liver disease.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Since both obesity and T2DM continue to rise, it is expected that NAFLD will reach epidemic proportions worldwide. The prevalence of ultrasound-defined NAFLD ranges from 14 to 45%.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In Spain, Caballeria et al., in a recent cross-sectional study, showed a prevalence of 26% in individuals aged 15 and 85 years randomly selected from 25 Primary Healthcare Centers,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> consistent with previous estimates.</p><p id="par0015" class="elsevierStylePara elsevierViewall">A genetic underpinning for NAFLD has been suggested by familial aggregation studies,<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,16</span></a> heritability studies,<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17,18</span></a> candidate gene studies,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> genome-wide scans<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19–22</span></a> and expression studies.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23–27</span></a> The presence of a genetic basis in NAFLD is important in order not only to identify, individuals at risk, but also to dissect NAFLD pathogenesis and the development of new therapies.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The ultimate goal of this review is to provide the most recent studies in the genetic epidemiology of NAFLD and its association with metabolic traits, namely, adiposity/obesity, insulin resistance, and dyslipidemia. The review is structured in two parts: first, the author will provide some background concepts in genetic epidemiology and the current understanding of NAFLD pathophysiology; and, secondly, the reviewer will show the most up-to-date findings in humans in candidate gene studies and genome wide association studies (GWAS) and their association with metabolic traits. This paper, however, will not assess other forms of fatty liver disease, expression studies or animal studies.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Concepts in genetic epidemiology of NAFLD</span><p id="par0025" class="elsevierStylePara elsevierViewall">NAFLD is considered a complex disease, that is, there is no simple Mendelian pattern of single-gene inheritance such as maturity onset diabetes of the young. In NAFLD, multiple genes, environmental factors, age effects, and their interactions, may be involved.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Genetic epidemiology studies can be divided in two broad categories: (a) according to the relationships between participants (family-based <span class="elsevierStyleItalic">versus</span> non-related or population-based); and, (b) according to the knowledge of the genetic marker(s) used (hypothesis-driven or candidate gene study <span class="elsevierStyleItalic">versus</span> hypothesis free or genome wide association study). A candidate gene is defined as a gene in which its product is considered to play a role in disease pathogenesis.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> It is important to bear in mind that all studies provide key information and are not mutually exclusive. For instance, family-based studies are typically the first step in determining whether a condition is genetic in nature, the model of inheritance, and to understand the proportion of phenotypic variance due to shared genetic factors (heritability). Family-based studies may use <span class="elsevierStyleItalic">linkage analysis</span> to identify the location of a major gene or, association analyses such as the transmission-disequilibrium test, candidate gene approach and a genome-wide association analysis.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Population-based studies, on the other hand, are the mainstream of studies in NAFLD and, until recently, the candidate gene study was the most common design using the “two hit” hypothesis as a framework.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Both candidate gene and GWAS rely on the statistical association of genetic markers and the disease (phenotype) of interest. The most commonly used genetic markers are the single nucleotide polymorphisms or SNPs, defined as a change in a single base pair of the DNA common in more than 1% of the population.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The major problem in both candidate gene and GWAS is the presence of false negative and false positive associations. The interpretation of a negative study in genetics is challenging, but most of the time, the problem is a lack of statistical power, that is, true associations are not detected in the study. Consequently, power calculation will provide a robust answer whether the association is indeed possible or not. In GWAS, where there is no hypothesis behind the statistical analysis, the problem we encounter is the opposite, and we commonly find spurious associations due to chance, even after statistical correction for multiple comparisons. As a result, most of the genetics journals in the same paper need to replicate newly associated genes in different, independent samples (known as ‘replication’). The final step is gene fine sequencing to understand what the mechanism is for the association of this particular gene, and use of animal models (knock-outs) and in vitro studies to characterize the metabolic effect of that particular mutation.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Current understanding of NAFLD pathogenesis</span><p id="par0050" class="elsevierStylePara elsevierViewall">The key pathological finding in fatty liver disease is the accumulation of triglycerides in the hepatocytes due to a disproportion between triglycerides acquisition and removal.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32,33</span></a> The key component of triglyceride is the long-chain fatty acid. The major routes of free fatty acids (FFA) are (a) dietary intake; (b) lipolysis from fat reservoirs, and (c) <span class="elsevierStyleItalic">de novo</span> lipogenesis. Animal and human inherited diseases have shown increased hepatic steatosis with increased triglyceride dietary intake, increased lipolysis from peripheral tissues, increased <span class="elsevierStyleItalic">de novo</span> lipogenesis, or prevention of triglyceride removal from the liver (i.e. decreased efflux or oxidation).<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The exact contributions of each pathway to the development of hepatic steatosis have been studied by Donnelly et al.,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> who showed that 59% of hepatic fat derived from circulating FFAs (mainly lipolysis), 26% from <span class="elsevierStyleItalic">de novo</span> lipogenesis and 15% from diet. The latter mechanism is particularly interesting in the context of obesity and frequent consumption of refined sugars. Increased glucose intake has been associated with hepatic steatosis due to the <span class="elsevierStyleItalic">de novo</span> synthesis of free fatty acids by increased insulin (up-regulator of the transcription factor sterol regulatory element-binding protein-1c, SREBP-1c), availability of substrate and the activation of the transcription factor carbohydrate responsive element-binding protein (ChREBP), involved in the expression of lipogenic genes.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32,33</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Insulin resistance is an essential key etiopathogenic factor in the development and progression of fatty liver. Whether insulin resistance is a cause of hepatic steatosis, or vice versa, is a matter of debate and has been reviewed recently.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> According to Cohen et al.,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> current evidence suggests that insulin resistance comes <span class="elsevierStyleItalic">first</span> and leads to hepatic steatosis, as shown by animal models and human diseases where hepatic steatosis is not associated with insulin resistance and, conversely, human diseases with inherited insulin resistance lead to hepatic steatosis (e.g. <span class="elsevierStyleItalic">AKT2</span> mutation). Opposite views, however, suggested that hepatic steatosis, possibly originated by impaired mitochondrial β-oxidation of fatty acids, leads to hepatic insulin resistance which, in turn, increases <span class="elsevierStyleItalic">de novo</span> fatty acid synthesis, impairs gluconeogenesis, hepatic glucose uptake, transport of lipoproteins perpetuating increase peripheral insulin resistance.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13,33</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">A “two-hit model” for the development of steatohepatitis was proposed by Day and James in 1998. In their view, the first step was the accumulation of free fatty acids in the liver, and, from there, further insults induced inflammation, fibrosis and, eventually, cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Nevertheless, Dr. Day's group, based on current evidence from animal models, updated their own hypothesis and suggested that “steatosis may be early adaptive response to hepatocyte stress through which potentially lipotoxic FFAs are partitioned into relatively stable intracellular triglyceride stores”.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> NAFLD is now seen “as a combination of effects of several fundamental biochemical and immunological mechanisms of liver injury rather than adhering to a sequential ‘two-hit’ paradigm”.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In summary, based on Day et al., “insulin resistance promotes increased hepatic FFA flux (lipolysis, diet and lipogenesis) leading to hepatic steatosis, and is driven by (1) direct hepatocyte lipotoxicity, (2) hepatocellular oxidative stress secondary to free radicals produced during b- and -FFA oxidation, (3) endotoxin/TLR4-induced inflammation, (4) cytokine release, and (5) endoplasmic reticulum (ER) stress”, finally leading to inflammation, cellular damage, and progression to cirrhosis.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">A systematic approach to reviewing the genetic epidemiology of NAFLD</span><p id="par0070" class="elsevierStylePara elsevierViewall">In order to identify most of the available published literature on the genetics of NAFLD, the author performed a systematic search using PUBMED, by applying the following engine: (polymorphism OR SNP) AND (“steatosis” OR “steatohepatitis” OR NAFLD OR NASH) without language restriction and up to July 26th, 2011. Studies were included and analyzed if they were performed on humans. The search yielded 224 references, of which 60 corresponded to candidate gene studies and are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, and three genome wide association studies (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). This search engine did not use the more ‘non-English language friendly’ database EMBASE, and was limited by the published papers (risk of publication bias since negative studies usually remain unpublished). Genes (or nearby genes) are named using the HUGO Gene Nomenclature Committee (HGNC) and reported identification number.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Candidate genes studies in human NAFLD: hepatic lipid metabolism, insulin resistance and oxidative stress</span><p id="par0075" class="elsevierStylePara elsevierViewall">Numerous candidate gene studies applying this ‘multiple-hit’ hypothesis, have studied the effects of genes on NAFLD presence and progression. The reviewer has simplified the previous hypothesis into the following mechanisms (not mutually exclusive): genes involved in hepatic lipid metabolism (synthesis, storage, export, oxidation), genes implicated in insulin signaling (insulin resistance), and finally, genes involved in oxidative stress and inflammation (and therefore, most likely involved in progression to cirrhosis) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The reviewer included, when appropriate, other data from different metabolic traits to illustrate the direction of association for a particular gene (in parenthesis). Interestingly, the strongest signals for other well-known risk factors, such as obesity or diabetes (e.g. <span class="elsevierStyleItalic">FTO</span>, <span class="elsevierStyleItalic">TCF7L2</span>) did not associate with fatty liver disease, suggesting that fatty liver disease, on its own, has other genetic underpinnings.</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hepatic lipid metabolism</span><p id="par0080" class="elsevierStylePara elsevierViewall">The alteration in the management of triglycerides handling would likely lead to the development of hepatic steatosis. One of the most promising candidate genes was the microsomal triglyceride transfer protein (<span class="elsevierStyleItalic">MTTP</span>, 7467) central in lipoprotein role assembly and its inhibition in familial hypercholesterolemia was shown to increase liver steatosis. Unfortunately, this review showed inconsistent association with fatty liver disease and a marginal effect on related metabolic traits, suggesting that it is not clearly implicated in the development of fatty liver disease, or that the studies lack power to detect any differences. Other natural metabolic pathways in lipid metabolism, such as lipoprotein metabolism and hepatic lipase activity, have yielded similar inconsistent associations with hepatic steatosis (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Insulin sensitivity</span><p id="par0085" class="elsevierStylePara elsevierViewall">NAFLD has been considered the liver component of the metabolic syndrome and, therefore, insulin resistance is supposed to be a key etiopathogenetic factor. Adiponectin is a cytokine with insulin-sensitizing, antifibrogenic and anti-inflammatory roles and, in histology, hypoadiponectinemia, have been associated with advanced NAFLD. As shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, the association with steatosis is inconsistent with adiponectin polymorphisms.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Iron overload, commonly associated with progression of liver disease, insulin resistance and oxidative stress, have been suggested to play a role in the development and progression of NAFLD. Our recent meta-analysis has shown that the hemochromatosis gene (<span class="elsevierStyleItalic">HFE</span>) has no association with the NAFLD or advanced NASH.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Finally, other appealing genes such as <span class="elsevierStyleItalic">PPARG</span> or <span class="elsevierStyleItalic">TCF7L2</span> have been associated with either liver steatosis and metabolic traits, however, the bulk of the literature shows minimal association, and warrants more research. Recently, a GWAS consortium have shown that, except for the <span class="elsevierStyleItalic">GCKR</span>, none of the reported candidate genes in NALFD has been associated with levels of A1c highlighting that fat accumulation may represent a different type of individual with diabetes.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Oxidative stress</span><p id="par0095" class="elsevierStylePara elsevierViewall">The association with polymorphisms associated with oxidative stress would help in understanding the progression of NAFLD to NASH/cirrhosis and, through oxidation of lipoproteins, its association with cardiovascular disease. Up to date, there is no strong evidence to pinpoint a particular polymorphism associated with progression of liver disease or associated with oxidation of lipoproteins (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p></span></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Genome wide association studies in fatty liver disease</span><p id="par0100" class="elsevierStylePara elsevierViewall">In 2008, Romeo et al. were the first to apply the GWAS method using a phenotype based on magnetic resonance spectroscopy.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> They studied 9,299 non-synonymous sequence variations and identified a missense mutation [Ile148<span class="elsevierStyleHsp" style=""></span>→<span class="elsevierStyleHsp" style=""></span>Met148 (I148M)] in a patatin-like phospholipase domain-containing (PNPLA) 3 gene <span class="elsevierStyleItalic">PNPLA3</span> (HCNG: 18590). <span class="elsevierStyleItalic">PNPLA3</span>, highly expressed in adipose tissue and liver, is regulated by insulin through a signaling cascade that includes LXR and SREBP-1c<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and, therefore, increased with feeding in animal studies.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> This mutation is, by far, the strongest genetic signal up to date and showed a increased odds ratio for fatty liver of 3.26 in the original report.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In addition, the PNPLA3 gene could also be responsible for the difference in prevalence of fatty liver disease between ethnic groups. For instance, Mexican-Americans have a higher prevalence of the high risk allele, whereas African Americans, where fatty liver is known to be less frequent, had a protective variation for such.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Further studies confirmed the association between this gene and the presence of fatty liver disease, including GWAS with liver enzymes<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> and multiple case-control studies<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><p id="par0105" class="elsevierStylePara elsevierViewall">Chalasani et al.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> described, in 236 white female biopsy-proven NAFLD patients, five new genetic variants associated with inflammation and fibrosis: a variant in the <span class="elsevierStyleItalic">FDFT1</span> (farnesyl diphosphate farnesyl transferase 1, HGNCI 3629) was correlated with NAFLD; in addition, they found an association with lobular inflammation for the collagen gene <span class="elsevierStyleItalic">COL13A1</span> (collagen, type XIII, alpha 1, HGNC 2190), a SNP near the <span class="elsevierStyleItalic">PDGFA</span> gene (platelet-derived growth factor alpha polypeptide, HGNC 8799); the <span class="elsevierStyleItalic">LTBP3</span> (latent transforming growth factor beta-binding protein 3, HGNC 6716), and the <span class="elsevierStyleItalic">EFCAB4B</span> (EF-hand calcium binding domain 4B, HGNC: 28657, <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><p id="par0110" class="elsevierStylePara elsevierViewall">Most recently, we showed, in the Genetics of Obesity-related Liver Disease (GOLD) Consortium, four additional genetic variants in addition to the <span class="elsevierStyleItalic">PNPLA3</span> (HGNC: 18590), namely, <span class="elsevierStyleItalic">NCAN</span> (neurocan, HGNC: 2465), <span class="elsevierStyleItalic">LYPLAL1</span> (lysophospholipase-like 1, HGNC: 20440); <span class="elsevierStyleItalic">GCKR</span> (glucokinase regulatory protein, HGNC: 4196); and the <span class="elsevierStyleItalic">PPP1R3B</span> (protein phosphatase 1, regulatory subunit 3b, HGNC: 14942), <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>. <span class="elsevierStyleItalic">GCKR</span> and <span class="elsevierStyleItalic">PPP1R3B</span> are key enzymes in <span class="elsevierStyleItalic">de novo</span> lipogenesis from glucose and <span class="elsevierStyleItalic">LYPLAL1</span>-related protein, and make them plausible for having a role in consecutive steps in triglyceride breakdown. The role of <span class="elsevierStyleItalic">NCAN</span> remains to be determined and has been associated with lipid traits.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Interestingly, we found that <span class="elsevierStyleItalic">PNPLA3</span> had a modest role in lipid metabolism, suggesting that these genes, if they are involved in lipid metabolism, exert their liver effects within the liver through different mechanistic pathways than those observed by conventional laboratory lipid measurement. In addition, <span class="elsevierStyleItalic">PNPLA3</span> has been shown to have a null effect on insulin sensitivity, or, surprisingly an insulin-sensitizing effect in obese carriers,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> consistent with the current hypothesis that fat in the liver does not lead to insulin resistance and may be a protective stage. A recent GWAS showed, however, that A1c levels were associated with GCKR mutations and, therefore, this would be a common link in why patients with NAFLD have increased levels of A1c compared to the general population.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Future directions: candidate gene studies</span><p id="par0115" class="elsevierStylePara elsevierViewall">Old and new genes have been reported in association with NAFLD, and all show the same problem: the need for replication. The major caveat of candidate gene studies is the lack of power. For instance, assuming a genetic risk ratio of 1.5 for a given polymorphism (high for most of the replicated genetic studies), and a allele frequency of about 20%, more than 400 patients and controls are required to give a study 90% power to detect a significant effect at the 5% level.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Day<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> and Bataller<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> provide two outstanding reviews to guide the reader in the design of high quality candidate gene studies, step-by-step.</p><p id="par0120" class="elsevierStylePara elsevierViewall">On the other hand, if the researcher is willing to invest his/her time to study new candidate genes, then Day proposes to find them by reviewing: “(1) gene product considered to play a role in the disease; (2) gene is known to be mutated in a familial form of the disease, (3) gene knockout/overexpression in animal models influences disease development; (4) gene lies in a chromosomal region associated with disease in a linkage study; (5) gene expression is altered in microarray studies of tissue from patients with disease; (6) gene is identified in a phenotype-driven mouse mutagenesis study”<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>; and (7) gene identified in genome-wide association studies.</p><p id="par0125" class="elsevierStylePara elsevierViewall">In conclusion, genes play a role in the development and progression of NAFLD; <span class="elsevierStyleItalic">PNPLA3</span> is the strongest signal up to date, but there are other numerous genes that have been described but not formally replicated. Candidate genes for metabolic traits have yielded conflicting results in their association with NAFLD. Therefore, the future of genetic epidemiology will require replication and, ultimately, expression studies and animal models to know the molecular role of that particular genetic variant. The understanding of genetic determinants of NAFLD will help to identify individuals at risk and, potentially, new therapies to treat the most common chronic liver disease in the world.</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interests</span><p id="par0130" class="elsevierStylePara elsevierViewall">The author declares no conflict of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres108575" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec95997" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres108574" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec95998" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Brief epidemiology and genetic basis of non-alcoholic fatty liver disease" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Concepts in genetic epidemiology of NAFLD" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Current understanding of NAFLD pathogenesis" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "A systematic approach to reviewing the genetic epidemiology of NAFLD" "secciones" => array:1 [ 0 => array:3 [ "identificador" => "sec0025" "titulo" => "Candidate genes studies in human NAFLD: hepatic lipid metabolism, insulin resistance and oxidative stress" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Hepatic lipid metabolism" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Insulin sensitivity" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Oxidative stress" ] ] ] ] ] 8 => array:3 [ "identificador" => "sec0045" "titulo" => "Genome wide association studies in fatty liver disease" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Future directions: candidate gene studies" ] ] ] 9 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interests" ] 10 => array:2 [ "identificador" => "xack36416" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-09-14" "fechaAceptado" => "2011-11-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec95997" "palabras" => array:6 [ 0 => "Genetic association studies" 1 => "Non-alcoholic fatty liver disease" 2 => "Fatty liver" 3 => "Insulin resistance" 4 => "Obesity" 5 => "Review" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec95998" "palabras" => array:6 [ 0 => "Estudios geneticos de asociación" 1 => "Enfermedad grasa del higado no alcoholica" 2 => "Higado graso" 3 => "Insulino resistencia" 4 => "Obesidad" 5 => "Revision" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Whereas insulin resistance and obesity are considered major risk factors for the development and progression of NAFLD, the genetic underpinnings remain to be established. Before 2008, numerous candidate gene studies, based on prior knowledge of the pathophysiology of fatty liver, published numerous papers with conflicting results. In 2008, Romeo et al. published the first genome wide association study (GWAS), reporting the strongest genetic signal for fatty liver (<span class="elsevierStyleItalic">PNPLA3</span>, patatin-like phospholipase domain containing 3; rs738409). Most of the candidate genes and GWAS associations, however, have not been replicated and, therefore, its significance remains undetermined. Moreover, the associations between candidate genes and metabolic traits have yielded mixed results. This review summarizes the current understanding of genetic epidemiology of NAFLD and associated metabolic traits, namely, insulin resistance, adiposity and lipid disorders.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad de hígado graso no alcohólica es la enfermedad crónica del hígado más frecuente en el mundo. Considerando que la resistencia a la insulina y la obesidad son los factores de riesgo importantes para el desarrollo y progresión del hígado graso no alcohólico, las bases genéticas aún no se han establecido. Antes de 2008, se realizaron numerosos estudios de genes candidatos basándose en el conocimiento previo de la fisiopatología del hígado graso. Sin embargo, los resultados han sido contradictorios. En 2008, Romeo et al. publicó el primer estudio de asociación genómica amplia, descubriendo la señal genética más robusta para el hígado graso (PNPLA3, <span class="elsevierStyleItalic">patatin-like phospholipase domain containing 3</span>; rs738409). La mayoría de las asociaciones de genes candidatos y estudioa de asociación genómica amplia, sin embargo, no se han reproducido y, por tanto, su importancia sigue siendo indeterminada. Por otra parte, las asociaciones entre genes y rasgos metabólicos han arrojado resultados mixtos. Esta revisión resume el conocimiento actual de la epidemiología genética de hígado graso no alcohólica y trastornos asociados rasgos metabólicos, es decir, sensibilidad a la insulina, la adiposidad y los lípidos.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Parenthesis denotes studies done with metabolic traits but not with liver steatosis</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Gene (HGNC), SNP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Fatty liver \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Inflammation/fibrosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Insulin resistance (*) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Adiposity (*) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Lipids (*) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Hepatic lipid metabolism</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">PEMT</span> (8830),<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43–46</span></a> phosphatidylethanolamine N-methyltransferase; rs7946 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">MTTP</span> (7467),<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47–51</span></a> microsomal triglyceride transfer protein; rs1800591 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑↑↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑ (↓<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑↑ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">APOC3</span> (610),<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53,54</span></a> apolipoprotein C-III; rs2854116/2854117 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑∅(↑<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">FABP2</span> (2556),<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56,57</span></a> fatty acid binding protein 2, intestinal; rs1799883 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(↑<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(∅<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(↑<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">DGAT</span> (2843),<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> acyl-CoA:diacylglycerol acyltransferase; rs1944438 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ (∅<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ACSL4</span> (3571),<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> acyl-CoA synthetase long-chain family member 4; rs7887981 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADRB3</span> (288),<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> adrenergic, beta-3-, receptor; rs4994 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(↑<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(∅<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(↑<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADRB2</span> (286),<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> adrenergic, beta-2-, receptor, surface; rs1042714 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(∅<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(∅<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">LIPC</span> (6619),<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43,72</span></a> hepatic lipase; rs1800588 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">73,74,41,75</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">APOE</span> (613),<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">76–79</span></a> apolipoprotein E; N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑↓↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑↑(∅<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a>↑<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CLOCK</span> (2082),<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> clock homolog (mouse); rs11932595 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(↑<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Insulin sensitivity</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ENPP1 (3356),<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47,83</span></a> ectonucleotide pyrophosphatase/phosphodiesterase 1 or PC-1; rs1044498 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅(↑<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">84,85</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅(↑<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IRS1</span> (6125),<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a> insulin receptor substrate 1; rs1801278 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(∅<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">87,88</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ADIPOQ</span> (13633),<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">89–92</span></a> adiponectin, C1Q and collagen domain containing; rs2241766 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅∅↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑↑(↑<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">93–95</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑(↑<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑↑↑ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Insulin sensitivity</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">PPARA</span> (9232),<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">97,98</span></a> peroxisome proliferator-activated receptor alpha, rs1800206 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>PPARG (9236),<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> peroxisome proliferative activated receptor, gamma; rs3856806 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">PPARG</span>, <a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">97,99</span></a> rs1801282 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ ↓ (↓<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">100–104</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(↑<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">103</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ (↑<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">105</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">PPARGC1A</span> (9237),<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> peroxisome proliferator-activated receptor gamma, coactivator 1 alpha; rs8192687 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(∅<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">106</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">TCF7L2</span> (11641),<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">107</span></a> transcription factor 7-like 2 (T-cell specific, HMG-box); rs7903146 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(↑<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">108–111,102</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">GCKR</span> (4196),<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">112</span></a> glucokinase (hexokinase 4) regulator; rs780094 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">113,114,110,115–117</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(↑<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">113,114,110,115–117</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">MC4R</span> (6932),<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">118</span></a> melanocortin-4 receptor; rs17782313 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(↓<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">119–124</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SPINK</span>-1 (11244),<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">125</span></a> Serine protease inhibitor Kazal-1; N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">LEPR</span> (6554),<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">126</span></a> leptin receptor gene; N/A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">127</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(∅<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">128–130</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">LEP</span> (6553),<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> leptin; rs7799039 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(∅<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">96,131</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Genes influencing generation of reactive oxidant species, or cytokine genes</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">TNF</span> (11892),<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43,92,132–135</span></a> Tumor necrosis factor-alpha; rs180062 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑↑∅∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅∅(↑<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">136</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅(↑<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">136</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">IL-6</span> (6018),<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> rs1800795 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑(∅<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">137</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(↑<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">138</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CD14 (</span>1628),<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">139</span></a> rs2569190 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">140</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SOD2</span> (11180),<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50,51,141</span></a> superoxide dismutase 2, mitochondrial; rs4880 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅↑↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">HFE</span> (4886),<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> hemochromatosis; rs1800562, rs1799945 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(↑<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ABCB11</span> (42),<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">142</span></a> ATP-binding cassette, subfamily B, member 11; rs2287622 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CFTR</span>/<span class="elsevierStyleItalic">MRP</span> (53),<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">143</span></a> ATP-binding cassette, sub-family C, member 2; rs17222723 rs8187710 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab195700.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Candidate gene studies in non-alcoholic fatty liver disease and its association with metabolic traits.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Parenthesis denotes studies done with metabolic traits but not with liver steatosis</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Gene (HGNC) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">SNP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Fatty liver \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Inflammation/fibrosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Insulin resistance (*) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Adiposity (*) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Lipids (*) \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PNPLA3</span> (18590), patatin-like phospholipase domain containing 3<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs738409 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅(↑<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">144</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">∅ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑∅<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PNPLA3</span> (18590), patatin-like phospholipase domain containing 3<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6006460 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↓ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">FDFT1</span> (3629),<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> farnesyl diphosphate farnesyl transferase 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2645424 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">COL13A1</span> (2190),<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> collagen, type XIII, alpha 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs1227756 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PDGFA</span> (8799),<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> platelet-derived growth factor alpha polypeptide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs343064 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">LTBP3</span> (6716),<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> latent transforming growth factor beta binding protein 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs1227756 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">EFCAB4B</span> (28657),<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> EF-hand calcium binding domain 4B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs887304 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">NCAN</span> (2465),<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> neurocan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2228603 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41,145</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">LYPLAL1</span> (20440),<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> lysophospholipase-like 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs12137855 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRefs" href="#bib0730"><span class="elsevierStyleSup">146–149</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">GCKR</span> (4196),<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> glucokinase regulatory protein \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs780094 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">113,114,110,115–117</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">113,114,110,115–117</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">PPP1R3B</span> (14942),<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> protein phosphatase 1, regulatory subunit 3b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs4240624 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">↑ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">150</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(↑<a class="elsevierStyleCrossRefs" href="#bib0755"><span class="elsevierStyleSup">151,152</span></a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab195701.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Genome wide association studies in nonalcoholic fatty liver disease and associated metabolic traits.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:152 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The epidemiology of nonalcoholic fatty liver disease: a global perspective" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0028-1091978" "Revista" => array:6 [ "tituloSerie" => "Semin Liver Dis" "fecha" => "2008" "volumen" => "28" "paginaInicial" => 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Program</span> (<span class="elsevierStyleGrantNumber" refid="gs0005">7-07-MN-08</span>, PI: Dr. Frederick L. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 101 | 8 | 109 |
| 2024 September | 169 | 13 | 182 |
| 2024 August | 110 | 9 | 119 |
| 2024 July | 107 | 4 | 111 |
| 2024 June | 117 | 7 | 124 |
| 2024 May | 108 | 7 | 115 |
| 2024 April | 115 | 6 | 121 |
| 2024 March | 89 | 7 | 96 |
| 2024 February | 92 | 18 | 110 |
| 2024 January | 145 | 8 | 153 |
| 2023 December | 99 | 10 | 109 |
| 2023 November | 85 | 6 | 91 |
| 2023 October | 101 | 18 | 119 |
| 2023 September | 88 | 22 | 110 |
| 2023 August | 75 | 5 | 80 |
| 2023 July | 128 | 12 | 140 |
| 2023 June | 64 | 2 | 66 |
| 2023 May | 139 | 12 | 151 |
| 2023 April | 108 | 8 | 116 |
| 2023 March | 107 | 5 | 112 |
| 2023 February | 49 | 3 | 52 |
| 2023 January | 80 | 12 | 92 |
| 2022 December | 39 | 9 | 48 |
| 2022 November | 75 | 26 | 101 |
| 2022 October | 48 | 18 | 66 |
| 2022 September | 39 | 17 | 56 |
| 2022 August | 74 | 12 | 86 |
| 2022 July | 50 | 10 | 60 |
| 2022 June | 116 | 12 | 128 |
| 2022 May | 72 | 8 | 80 |
| 2022 April | 49 | 17 | 66 |
| 2022 March | 70 | 12 | 82 |
| 2022 February | 61 | 3 | 64 |
| 2022 January | 68 | 9 | 77 |
| 2021 December | 49 | 7 | 56 |
| 2021 November | 42 | 15 | 57 |
| 2021 October | 61 | 13 | 74 |
| 2021 September | 45 | 16 | 61 |
| 2021 August | 47 | 6 | 53 |
| 2021 July | 37 | 6 | 43 |
| 2021 June | 50 | 9 | 59 |
| 2021 May | 39 | 10 | 49 |
| 2021 April | 108 | 36 | 144 |
| 2021 March | 70 | 15 | 85 |
| 2021 February | 33 | 17 | 50 |
| 2021 January | 49 | 22 | 71 |
| 2020 December | 37 | 11 | 48 |
| 2020 November | 53 | 12 | 65 |
| 2020 October | 40 | 11 | 51 |
| 2020 September | 40 | 16 | 56 |
| 2020 August | 52 | 30 | 82 |
| 2020 July | 31 | 12 | 43 |
| 2020 June | 34 | 14 | 48 |
| 2020 May | 43 | 23 | 66 |
| 2020 April | 43 | 8 | 51 |
| 2020 March | 71 | 21 | 92 |
| 2020 February | 68 | 18 | 86 |
| 2020 January | 85 | 13 | 98 |
| 2019 December | 64 | 14 | 78 |
| 2019 November | 44 | 15 | 59 |
| 2019 October | 63 | 13 | 76 |
| 2019 September | 52 | 23 | 75 |
| 2019 August | 43 | 16 | 59 |
| 2019 July | 51 | 17 | 68 |
| 2019 June | 75 | 27 | 102 |
| 2019 May | 181 | 28 | 209 |
| 2019 April | 61 | 36 | 97 |
| 2019 March | 23 | 9 | 32 |
| 2019 February | 27 | 16 | 43 |
| 2019 January | 17 | 13 | 30 |
| 2018 December | 18 | 9 | 27 |
| 2018 November | 20 | 8 | 28 |
| 2018 October | 21 | 13 | 34 |
| 2018 September | 34 | 10 | 44 |
| 2018 August | 13 | 6 | 19 |
| 2018 July | 8 | 3 | 11 |
| 2018 June | 12 | 9 | 21 |
| 2018 May | 6 | 5 | 11 |
| 2018 April | 14 | 12 | 26 |
| 2018 March | 15 | 0 | 15 |
| 2018 February | 10 | 1 | 11 |
| 2018 January | 12 | 2 | 14 |
| 2017 December | 9 | 0 | 9 |
| 2017 November | 11 | 3 | 14 |
| 2017 October | 14 | 2 | 16 |
| 2017 September | 13 | 10 | 23 |
| 2017 August | 13 | 2 | 15 |
| 2017 July | 25 | 6 | 31 |
| 2017 June | 30 | 6 | 36 |
| 2017 May | 40 | 8 | 48 |
| 2017 April | 20 | 3 | 23 |
| 2017 March | 16 | 32 | 48 |
| 2017 February | 16 | 1 | 17 |
| 2017 January | 36 | 4 | 40 |
| 2016 December | 33 | 4 | 37 |
| 2016 November | 34 | 5 | 39 |
| 2016 October | 39 | 10 | 49 |
| 2016 September | 25 | 2 | 27 |
| 2016 August | 31 | 4 | 35 |
| 2016 July | 36 | 5 | 41 |
| 2016 June | 44 | 8 | 52 |
| 2016 May | 32 | 7 | 39 |
| 2016 April | 30 | 10 | 40 |
| 2016 March | 40 | 12 | 52 |
| 2016 February | 45 | 13 | 58 |
| 2016 January | 36 | 6 | 42 |
| 2015 December | 34 | 7 | 41 |
| 2015 November | 34 | 8 | 42 |
| 2015 October | 33 | 6 | 39 |
| 2015 September | 24 | 10 | 34 |
| 2015 August | 53 | 3 | 56 |
| 2015 July | 42 | 3 | 45 |
| 2015 June | 20 | 3 | 23 |
| 2015 May | 22 | 6 | 28 |
| 2015 April | 27 | 5 | 32 |
| 2015 March | 25 | 5 | 30 |
| 2015 February | 21 | 1 | 22 |
| 2015 January | 35 | 4 | 39 |
| 2014 December | 66 | 8 | 74 |
| 2014 November | 33 | 1 | 34 |
| 2014 October | 53 | 4 | 57 |
| 2014 September | 39 | 3 | 42 |
| 2014 August | 34 | 2 | 36 |
| 2014 July | 44 | 4 | 48 |
| 2014 June | 31 | 1 | 32 |
| 2014 May | 37 | 3 | 40 |
| 2014 April | 24 | 3 | 27 |
| 2014 March | 63 | 6 | 69 |
| 2014 February | 47 | 4 | 51 |
| 2014 January | 42 | 6 | 48 |
| 2013 December | 54 | 2 | 56 |
| 2013 November | 60 | 2 | 62 |
| 2013 October | 59 | 6 | 65 |
| 2013 September | 37 | 2 | 39 |
| 2013 August | 55 | 3 | 58 |
| 2013 July | 43 | 7 | 50 |
| 2011 November | 491 | 0 | 491 |
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