GNPAT rs11558492 is not a Major Modifier of Iron Status: Study of Italian Hemochromatosis Patients and Blood Donors
Federico Greni*, Luca Valenti†, Raffaella Mariani‡, Irene Pelloni‡, Raffaela Rametta†, Fabiana Busti§, Giulia Ravasi*, Domenico Girelli§, Silvia Fargion†, Stefania Galimberti||, Alberto Piperno
, Sara Pelucchi*
,‡,¶,
Corresponding author
* School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
† Department of Medicine, Second Division of Gastroenterology, IRCCS, Ospedale Maggiore. Policlinico, University of Milano, Milano, Italy
‡ Centre for Disorder of Iron Metabolism, ASST-Monza-S.Gerardo Hospital, Monza, Italy
§ Department of Medicine Policlinico GB Rossi, University of Verona, Verona, Italy
|| Centre of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca, Monza, Italy
¶ Consortium for Human Molecular Genetics, Monza, Italy
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array:4 [ "autoresLista" => "Federico Greni, Luca Valenti, Raffaella Mariani, Irene Pelloni, Raffaela Rametta, Fabiana Busti, Giulia Ravasi, Domenico Girelli, Silvia Fargion, Stefania Galimberti, Alberto Piperno, Sara Pelucchi" "autores" => array:12 [ 0 => array:3 [ "nombre" => "Federico" "apellidos" => "Greni" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 1 => array:3 [ "nombre" => "Luca" "apellidos" => "Valenti" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">†</span>" "identificador" => "aff2" ] ] ] 2 => array:3 [ "nombre" => "Raffaella" "apellidos" => "Mariani" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">‡</span>" "identificador" => "aff3" ] ] ] 3 => array:3 [ "nombre" => "Irene" "apellidos" => "Pelloni" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">‡</span>" "identificador" => 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University of Milano-Bicocca, Monza, Italy" "etiqueta" => "*" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Department of Medicine, Second Division of Gastroenterology, IRCCS, Ospedale Maggiore. Policlinico, University of Milano, Milano, Italy" "etiqueta" => "†" "identificador" => "aff2" ] 2 => array:3 [ "entidad" => "Centre for Disorder of Iron Metabolism, ASST-Monza-S.Gerardo Hospital, Monza, Italy" "etiqueta" => "‡" "identificador" => "aff3" ] 3 => array:3 [ "entidad" => "Department of Medicine Policlinico GB Rossi, University of Verona, Verona, Italy" "etiqueta" => "§" "identificador" => "aff4" ] 4 => array:3 [ "entidad" => "Centre of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca, Monza, Italy" "etiqueta" => "||" "identificador" => "aff5" ] 5 => array:3 [ "entidad" => "Consortium for Human Molecular Genetics, Monza, Italy" "etiqueta" => "¶" "identificador" => "aff6" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Correspondece and reprint request:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 533 "Ancho" => 1361 "Tamanyo" => 46363 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Liver iron concentration according to GNPAT genotypes in hemochromatosis (HFE-HH) patients (whole cohort) (<span class="elsevierStyleBold">A</span>) and hemochro-matosis male-only patients (<span class="elsevierStyleBold">B</span>).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Introduction</span><p id="p0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HFE</span>-related Hemochromatosis (HH) is the most common inherited iron overload disease in Caucasian populations. Homozygosity for the p.C282Y mutation in <span class="elsevierStyleItalic">HFE</span> is the typical defect conferring a strong predisposition to develop the disease.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">1</span></a> It leads to inadequate production of hepcidin, the master regulator of iron homeostasis through a still incompletely understood mechanism.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">1</span></a> Several evidences indicate that p.C282Y homozygosity has variable penetrance and expression. While most homozy-gotes for the p.C282Y mutation show alteration of serum iron indices, severe iron overload and iron-related complications are observed in less than 30% of men and 5% of women.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">2-4</span></a> Alcohol intake and obesity, and coexistence with other diseases able to increase iron absorption or favour liver damage, can influence phenotype expression.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">5-9</span></a> The role of genetic modifiers was demonstrated in <span class="elsevierStyleItalic">HFE</span>-knock-out mice,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> but association studies between genetic markers and disease phenotype in humans have given conflicting results.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">11,16</span></a> Recently, McLaren, <span class="elsevierStyleItalic">et al</span>.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">17</span></a> identified glyceronephosphate O-acyltransferase <span class="elsevierStyleItalic">(GNPAT)</span> rs11558492 A > G polymorphism (p.D519G) as a new potential genetic modifier of <span class="elsevierStyleItalic">HFE</span> hemochromatosis pheno-type in p.C282Y homozygotes. The prognostic role of this polymorphism has been evaluated in other cohorts,<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">18-20</span></a> but none demonstrated an association between the SNP and markers of iron overload. However, Besson-Fournier, <span class="elsevierStyleItalic">et al</span>. found allele G to be significantly enriched in the subset of males with markedly increased iron stores. More recently, in a small cohort of healthy women and in 59 individuals not carrying <span class="elsevierStyleItalic">HFE</span> genotypes 8 hours after iron challenge an association between minor (G) <span class="elsevierStyleItalic">GNPAT</span> al-lele and serum iron was reported.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">21,22</span></a> To contribute in understanding the role of this SNP as a possible modifier of iron phenotype, we analysed alleles and genotypes frequencies and their relationship with iron parameters in a cohort of 298 <span class="elsevierStyleItalic">HFE</span> p.C282Y homozygotes of Italian ancestry and a group of 169 male healthy blood donors.</p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Material and Methods</span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Patients</span><p id="p0015" class="elsevierStylePara elsevierViewall">Two hundred and ninety-eight patients (205 men and 93 women) homozygous for p.C282Y in <span class="elsevierStyleItalic">HFE</span> with a median age of 48 years (interquartile range (IQR) 36-57 years) were studied. They attended the Centre for Disorder of Iron Metabolism at ASST-Monza-S.Gerardo Hospital, Fondazione IRCCS Ca’ Granda Policlinico Hospital in Milan and Policlinico GB Rossi in Verona. Patients were selected based on availability of serum ferritin (SF), trans-ferrin saturation (TS), alcohol intake and serum alanine aminotransferase (ALT) at diagnosis, and good quality DNA. Patients with coexistent chronic liver diseases (al-pha-1 antitrypsin deficiency, autoimmune hepatitis, chronic B or C virus hepatitis), and alcohol intake > 50 g/day in men and > 30 g/day in women<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">23</span></a> were excluded.</p><p id="p0020" class="elsevierStylePara elsevierViewall">Two-hundred and twenty-six patients (160 men and 66 women) underwent to liver biopsy for diagnostic (before <span class="elsevierStyleItalic">HFE</span> testing) and/or prognostic aim. Liver fibrosis was assessed according to Ishak, <span class="elsevierStyleItalic">et al</span>.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">24</span></a> Liver iron concentration (LIC) was available in 191 (64%) patients and was measured on liver biopsy samples in fresh or deparaffinized specimens (N = 155) or by quantitative magnetic resonance (MR) as previously reported.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">25,26</span></a> The lower number of available LIC is explained by the fact that:<ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">•</span><p id="p0025" class="elsevierStylePara elsevierViewall">Biopsy samples were not always as long as needed to allow adequate LIC measurement.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">25</span></a></p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">•</span><p id="p0030" class="elsevierStylePara elsevierViewall">MR iron quantitation was implemented only recently n our centres.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">26</span></a></p></li></ul></p><p id="p0035" class="elsevierStylePara elsevierViewall">Iron removed (IR) after iron depletion was available in 234 (78.5%) patients and measured as previously reported.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">23</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">One hundred and sixty-nine Italian health blood donors, selected from a cohort previously studied to define revalence of <span class="elsevierStyleItalic">HFE</span> mutations in Italy,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">27</span></a> were also evaluated as controls. Selection was based on <span class="elsevierStyleItalic">HFE</span> genotype (only wild-type or p.H63D heterozygotes were retained), sex (females were excluded), availability of haemoglobin and SF at first blood donation, and good quality DNA.</p><p id="p0045" class="elsevierStylePara elsevierViewall">Patients gave their informed consent for liver biopsy and both patients and controls for using their DNAs previously collected for <span class="elsevierStyleItalic">HFE</span> testing according to Institutions’ policy. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in <span class="elsevierStyleItalic">a priori</span> approval by the appropriate institutional review committee.</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055"><span class="elsevierStyleItalic">GNPAT</span> polymorphism analysis</span><p id="p0050" class="elsevierStylePara elsevierViewall">Genomic DNA of patients and controls was extracted from peripheral blood leucocytes using the Wizard<span class="elsevierStyleSup">®</span> Genomic DNA Purification kit (Promega, Madison, WI, USA) or the ZR DNA-Card Extraction Kit™ (Zymo Research, Irvine, CA, USA) according to manufacturer's instructions. <span class="elsevierStyleItalic">GNPAT</span> rs11558492 genotyping was carried out by tetra-primer Amplification Refractory Mutation System (ARMS-PCR) and verified by 1.5% of agarose gel stained with ethidium bromide, and/or TaqMan<span class="elsevierStyleSup">®</span> 5’-nuclease assays (LifeTechnologies, Carlsbad, CA). Random samples were confirmed by direct sequencing.</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Statistical analysis</span><p id="p0055" class="elsevierStylePara elsevierViewall">Median and IQR were used for descriptive purposes as appropriate. Hardy-Weinberg equilibrium was examined for all subjects using χ<span class="elsevierStyleSup">2</span> test. To evaluate the prognostic role of <span class="elsevierStyleItalic">GNPAT</span> polymorphism, we evaluated allele and genotype frequencies according to TS, SF, LIC and IR levels in patients and SF levels in controls. In patients, analyses were performed in the whole series and in males only. A further analysis was done comparing subgroups of male patients with extreme phenotypes: severe iron overload (SF > 2,000 μg/L, IR > 10 g and/or LIC > 250 μmol/ g, alcohol intake < 30 g/day), mild iron overload (SF < 1000 μg/L, IR < 5 g and/or LIC < 100 μmol/g, alcohol intake < 30 g/day). To evaluate the effect of <span class="elsevierStyleItalic">GNPAT</span> rs11558492 on liver fibrosis we grouped patients in two groups: those with absent or mild-moderate fibrosis (stage 0-3) and with severe fibrosis-cirrhosis (stage 4-6) as previously reported.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">23</span></a> Comparisons of <span class="elsevierStyleItalic">GNPAT</span> rs11558492 al-lele and genotype frequencies between groups were done by Fisher's exact test. Statistical analyses were performed using GraphPad Prism software, version 4.0 (San Diego, CA, USA). P-value < 0.05 was the accepted level of significance.</p></span></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Results</span><p id="p0060" class="elsevierStylePara elsevierViewall">Genotype distributions of <span class="elsevierStyleItalic">GNPAT</span> rs11558492 were in Hardy-Weinberg equilibrium in patients and controls. <a class="elsevierStyleCrossRef" href="#t0010">Table 1</a> shows main data of <span class="elsevierStyleItalic">HFE</span>-HH patients and controls. Serum ferritin significantly correlated with LIC (R<span class="elsevierStyleSup">2</span> = 0.42; p < 0.0001) and IR (R<span class="elsevierStyleSup">2</span> = 0.6; p < 0.0001), and LIC with IR (R<span class="elsevierStyleSup">2</span> = 0.51; p < 0.0001). As shown in <a class="elsevierStyleCrossRef" href="#t0015">table 2</a>, genotype and allele frequencies were comparable in patients and healthy blood donors, and those reported in the Exome Variant Server (EVS) database (genotypes: AA = 64%; AG = 31.2%; GG = 4.8%; alleles: A = 79.7% and G = 20.3%).</p><elsevierMultimedia ident="t0010"></elsevierMultimedia><elsevierMultimedia ident="t0015"></elsevierMultimedia><p id="p0065" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#f0010">Figure 1</a> A-C shows median and IQR of SF according to <span class="elsevierStyleItalic">GNPAT</span> genotypes in the whole cohort [AA: 1,000 μg/L (552-1815.5); AG + GG: 1061 μg/L (610.5-1946.5)] and male-only [AA: 1145 μg/L (801-2019); AG + GG: 1245 μg/L (771-2721)] HH patients, and in controls [AA: 78.0 μg/L (55.5-117.5); AG + GG: 83.0 μg/L (53-110)]. No significant difference was observed. Accordingly, also LIC and IR did not differ according to <span class="elsevierStyleItalic">GNPAT</span> genotypes both in the whole cohort of HH patients [LIC: AA: 214.2 μmol/g (158.7-361.2); AG + GG: 242.6 μmol/g (167.2-310.2); IR: AA: 6.25 g (4-9.9); AG + GG: 5.77 g (3.9-10)] and in male-only subgroup [LIC: AA: 220 μmol/g (167.2-365.1); AG + GG: 263.1 μmol/g (179.4-320); IR: AA: 8 g (5-12); AG + GG: 8 g (4.7-11.7)] (Figures 2 A-B and 3 A-B). No differences were also observed for TS [AA genotype: 85% (72-91.6); AG + GG genotypes: 90% (76.7-97.5)], haemoglobin and ALT (data not shown). We then measured the frequency of <span class="elsevierStyleItalic">GNPAT</span> alleles and genotypes in the subgroups of patients with extreme phenotypes. Thirty and thirty-eight men fulfilled the criteria for severe and mild iron overload, respectively. Allele and genotype frequencies did not differ between the two subgroups (<a class="elsevierStyleCrossRef" href="#t0020">Table 3</a>) and compared to EVS database. Fifty-eight out of 226 patients had severe fibrosis/cirrhosis. Minor allele frequency (MAF) was slightly higher in patients with severe fibrosis/cirrhosis (25%) than in those with absent/mild fibrosis (20.5%), but not significantly so (p = 0.36). Similarly, in the subgroup of men with alcohol intake < 30 g/day, MAF was 25% <span class="elsevierStyleItalic">vs</span>. 19.1%, respectively (p = 0.31).</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><elsevierMultimedia ident="f0015"></elsevierMultimedia><elsevierMultimedia ident="f0020"></elsevierMultimedia><elsevierMultimedia ident="t0020"></elsevierMultimedia></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Discussion</span><p id="p0070" class="elsevierStylePara elsevierViewall">We evaluated the frequency of <span class="elsevierStyleItalic">GNPAT</span> alleles and genotypes in a cohort of Italian p.C282Y homozygous patients and healthy blood donors and the relation between the SNP and markers of iron status. The frequency of alleles and genotypes in patients did not differ compared to healthy blood donors and those reported in EVS database. Allele frequencies of <span class="elsevierStyleItalic">GNPAT</span> p.D519G were slightly lower than that reported in other series of HH patients originating from Western Europe,<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">18-20</span></a> but similar to that of European Americans from the EVS database. Also, we did not find associations between alleles and genotypes and TS, SF, LIC and IR in <span class="elsevierStyleItalic">HFE</span>-HH patients, and SF in blood donors. Our results contrast those reported by McLaren, <span class="elsevierStyleItalic">et al</span>.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">17</span></a> in North-American and Australian HH patients, but agree to those reported in other cohorts<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">18,19,28</span></a> of <span class="elsevierStyleItalic">HFE</span>-HH patients. Also, we could not find differences comparing al-lele and genotype frequencies in the subsets of <span class="elsevierStyleItalic">HFE</span>-HH patients selected for mild and severe iron phenotypes. We used restrictive criteria (SF > 2,000 μg/L and IR > 10 g and/or LIC > 250 μmol/g) to define severe iron pheno-type in <span class="elsevierStyleItalic">HFE</span>-HH, but similar results were observed even using a ferritin cut-off of 1,000 μg/L instead of 2,000 μg/L (N = 67 men with alcohol intake < 30 g/day; MAF: 23.1%).</p><p id="p0075" class="elsevierStylePara elsevierViewall">McLaren, <span class="elsevierStyleItalic">et al</span>.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">17</span></a> linked controversies to the design and power of studies and to inclusion criteria and supported the role of <span class="elsevierStyleItalic">GNPAT</span> as a modifier of iron phenotype showing that it might participate in hepcidin regulation through a still undefined mechanism <span class="elsevierStyleItalic">in vitro</span>. We hypothesised that analysing subjects of Italian ancestry whose genetic structure is heterogeneous might help in shedding light on these discrepancies.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">29</span></a> Our findings indicate that <span class="elsevierStyleItalic">GNPAT</span> rs11558492 is not a major modifier of iron status in <span class="elsevierStyleItalic">HFE</span>-HH, although we cannot exclude that it could be part of a more complex genetic background that might include more than one mild modifier.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">11,16</span></a> Accordingly, we were not able to show any relation between <span class="elsevierStyleItalic">GNPAT</span> polymorphism and iron status in healthy blood donors. The latter finding contrast those by Hsiao, <span class="elsevierStyleItalic">et al.</span><a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">21</span></a> who showed an association between serum iron at baseline and after an iron test in 83 young women. Similarly, Rametta, <span class="elsevierStyleItalic">et al.</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">22</span></a> demonstrated that carriers of the G variant without <span class="elsevierStyleItalic">HFE</span> genotypes at risk (p.C282Y wild type or p.H63D heterozygotes) have mildly increased iron absorption 8 hours after ferrous sulphate challenge. However, both studies did not find association between <span class="elsevierStyleItalic">GNPAT</span> and SF that represents the best marker of iron stores in healthy people. These results raised further questions on the clinical relevance of <span class="elsevierStyleItalic">GNPAT</span> as iron modifier. Last, <span class="elsevierStyleItalic">GNPAT</span> rs1155849 was not associated with severe fibrosis/cirrho-sis, confirming previous results.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">18</span></a> In conclusion, several evidence indicate that homozygosity for p.C282Y in <span class="elsevierStyleItalic">HFE</span> is necessary but not sufficient to develop significant iron overload. There is general agreement that acquired factors, such as alcohol intake, hepatic steatosis, obesity and coexistence of chronic viral hepatitis, are major modifiers of iron or clinical phenotype in HH.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">.</span><a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">9</span></a> Conversely, though milder effects cannot be ruled out in the absence of adequately powered cohorts, no polymorphisms that came up from studies done up to now seem to exert a major effect on iron phenotype to be considered for defining genetic susceptibility to fully penetrant <span class="elsevierStyleItalic">HFE</span>-HH in clinical practice. Interestingly, two recent studies strongly suggested a role for rs236918 in <span class="elsevierStyleItalic">PCSK7</span> gene as a modifier of risk of liver fibrosis in p.C282Y homozygotes.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">23,30</span></a> Exome or whole-genome sequencing studies by next-generation sequencing technologies will enable to further explore if there exist some other unknown genetic variants with clinical significance in <span class="elsevierStyleItalic">HFE</span>-HH patients carefully selected and controlled for environmental factors.</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Abbreviations</span><p id="p0080" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0015"><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">•</span><p id="p0085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ALT:</span> Serum alanine aminotransferase.</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">•</span><p id="p0090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ARMS-PCR:</span> Amplification refractory mutation system – polymerase chain reaction.</p></li><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">•</span><p id="p0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">EVS:</span> Exome variant server.</p></li><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">•</span><p id="p0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">GNPAT:</span></span> Glyceronephosphate O-acyltransferase.</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">•</span><p id="p0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HH:</span> Hereditary hemochromatosis</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">•</span><p id="p0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">IQR:</span> Interquartile range.</p></li><li class="elsevierStyleListItem" id="u0050"><span class="elsevierStyleLabel">•</span><p id="p0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">IR:</span> Iron removed.</p></li><li class="elsevierStyleListItem" id="u0055"><span class="elsevierStyleLabel">•</span><p id="p0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SF:</span> Serum ferritin.</p></li><li class="elsevierStyleListItem" id="u0060"><span class="elsevierStyleLabel">•</span><p id="p0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SNP:</span> Single nucleotide polymorphism.</p></li><li class="elsevierStyleListItem" id="u0065"><span class="elsevierStyleLabel">•</span><p id="p0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TS:</span> Transferrin saturation.</p></li></ul></p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">Conflict of Interest</span><p id="p0135" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Financial Support</span><p id="p0140" class="elsevierStylePara elsevierViewall">This work was partially supported by: Associazione per lo studio dell’Emocromatosi e delle Malattie da Sovracca-rico ONLUS +Fe, Monza, Italy; Ricerca Corrente Fon-dazione IRCCS Ca’ Granda Policlinico Milano, Italy; Associazione Malattie Metaboliche del Fegato ONLUS, Milano, Italy and Bando Medicina Molecolare 2014 Fon-dazione IRCCS Ca’ Granda Policlinico – Istituto Nazion-ale di Genetica Molecolare, Milan, Italy.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1197544" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Background and Aim" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Material and Methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1116230" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "s0010" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "s0015" "titulo" => "Material and Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "s0020" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "s0025" "titulo" => "GNPAT polymorphism analysis" ] 2 => array:2 [ "identificador" => "s0030" "titulo" => "Statistical analysis" ] ] ] 4 => array:2 [ "identificador" => "s0035" "titulo" => "Results" ] 5 => array:2 [ "identificador" => "s0040" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "s0045" "titulo" => "Abbreviations" ] 7 => array:2 [ "identificador" => "s0050" "titulo" => "Conflict of Interest" ] 8 => array:2 [ "identificador" => "s0055" "titulo" => "Financial Support" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-08-16" "fechaAceptado" => "2016-10-18" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1116230" "palabras" => array:5 [ 0 => "Glyceronephosphate O-acyltransferase" 1 => "Hereditary hemochromatosis" 2 => "Iron overload" 3 => "Polymorphism" 4 => "Serum ferritin" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015"><span class="elsevierStyleBold">Background and Aim</span></span><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">HFE</span>-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, <span class="elsevierStyleItalic">GNPAT</span> rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls.</p></span> <span id="abs0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020"><span class="elsevierStyleBold">Material and Methods</span></span><p id="sp0055" class="elsevierStyleSimplePara elsevierViewall">Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrho-sis.</p></span> <span id="abs0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025"><span class="elsevierStyleBold">Results</span></span><p id="sp0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">GNPAT</span> rs11558492 minor allele (G) frequency (MAF) was 20.3% in <span class="elsevierStyleItalic">HFE</span>-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in <span class="elsevierStyleItalic">HFE</span>-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis.</p></span> <span id="abs0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030"><span class="elsevierStyleBold">Conclusions</span></span><p id="sp0065" class="elsevierStyleSimplePara elsevierViewall">Our findings indicate that <span class="elsevierStyleItalic">GNPAT</span> rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in <span class="elsevierStyleItalic">HFE</span>-HH patients.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Background and Aim" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Material and Methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusions" ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 638 "Ancho" => 2074 "Tamanyo" => 85464 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Serum ferritin levels according to GNPAT genotypes in hemochromatosis (HFE-HH) patients (whole cohort) (<span class="elsevierStyleBold">A</span>), hemochromatosis male-only patients (<span class="elsevierStyleBold">B</span>) and healthy blood donors (<span class="elsevierStyleBold">C</span>).</p>" ] ] 1 => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 533 "Ancho" => 1361 "Tamanyo" => 46363 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Liver iron concentration according to GNPAT genotypes in hemochromatosis (HFE-HH) patients (whole cohort) (<span class="elsevierStyleBold">A</span>) and hemochro-matosis male-only patients (<span class="elsevierStyleBold">B</span>).</p>" ] ] 2 => array:7 [ "identificador" => "f0020" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 533 "Ancho" => 1361 "Tamanyo" => 47237 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Iron removed according to GNPAT genotypes in hemochromatosis (HFE-HH) patients (whole cohort) (<span class="elsevierStyleBold">A</span>) and hemochromatosis male-only patients (<span class="elsevierStyleBold">B</span>).</p>" ] ] 3 => array:7 [ "identificador" => "t0010" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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"><th 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" scope="col" style="border-bottom: 2px solid black">Variable \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">HFE</span>-HH (N = 298) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Healthy blood donors (N = 169) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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">Males \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">205 \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">169 \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">Age (years) \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">48 (36-57) \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">37 (31-48) \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">Transferrin saturation (%) \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">86 (71-95.5) \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">NA \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">Serum ferritin (mcg/L) \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">1000 (571-1828.5) \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">79 (54-116) \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">Iron removed<a class="elsevierStyleCrossRef" href="#tbl1fn1"><span class="elsevierStyleSup">†</span></a> (g) \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">6.6 (4-10) \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">Liver iron concentration (umol/g)<a class="elsevierStyleCrossRef" href="#tbl1fn2"><span class="elsevierStyleSup">††</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">218.6 (167.2-341.8) \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">Alanine aminotransferase (U/L) \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">40 (23-65) \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">NA \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2045081.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tbl1fn1" "etiqueta" => "†" "nota" => "<p class="elsevierStyleNotepara" id="np0010">Iron removed available in 234 out of 298 (78.5%).</p>" ] 1 => array:3 [ "identificador" => "tbl1fn2" "etiqueta" => "††" "nota" => "<p class="elsevierStyleNotepara" id="np0015">Liver iron concentration was available in 191 out of 298 (64 %). NA: not available.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Main data of <span class="elsevierStyleItalic">HFE</span>-HH patients and controls. Data are expressed as median (interquartile range).</p>" ] ] 4 => array:7 [ "identificador" => "t0015" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">No significant difference between patients and controls.</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"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">HFE</span>- HH (N = 298) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">HFE</span>- HH male-only (N = 205) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Healthy blood donors (N = 169) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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">Genotypes \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">AA \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">191 (64) \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">128 (62.4) \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">117 (69.2) \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">AG \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">93 (31.2) \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">67 (32.6) \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">46 (27.2) \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">GG Alleles \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">14 (4.8) \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">10 (5.0) \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">6 (3.6) \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">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">475 (79.7) \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">323 (78.7) \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">280 (82.8) \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">G \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">121 (20.3) \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">87 (21.3) \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">58 (17.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2045082.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Genotype and allele frequencies (number and percentage) of <span class="elsevierStyleItalic">GNPAT</span> rs11558492 polymorphism in <span class="elsevierStyleItalic">HFE</span>-HH patients (whole cohort and male-only) and healthy blood donors. Data are expressed as numbers and (percentages)</p>" ] ] 5 => array:7 [ "identificador" => "t0020" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">Severe iron overload: SF > 2000 μg/L, IR >10 g and/or LIC > 250 μmol/g, alcohol intake < 30 g/day. Mild iron overload: SF < 1,000 μg/L, IR < 5 g and/or LIC < 100 μmol/g, alcohol intake < 30 g/day).</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"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Alleles</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Genotypes</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col">A \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col">G \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col">AA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col">AG \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col">GG \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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">Severe iron overload (N = 30) \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">48 (80.0) \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">12 (20.0) \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">20 (66.6) \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">8 (26.6) \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">2 (6.8) \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">Mild iron overload (N = 38) \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">59 (76.6) \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">17 (22.4) \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">21 (55.2) \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">17 (44.8) \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">Total \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">107 \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">29 \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">41 \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">25 \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">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2045083.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">Allele and genotype frequencies in men with HH selected according to iron phenotype. Data are expressed as numbers and (percentages).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0010" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Haemochromatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Powell L.W." 1 => "Seckington R.C." 2 => "Deugnier Y." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(15)01315-X" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2016" "volumen" => "388" "paginaInicial" => "706" "paginaFinal" => "716" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26975792" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0015" "etiqueta" => "2." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 0 | 2 |
| 2024 October | 6 | 4 | 10 |
| 2024 September | 9 | 5 | 14 |
| 2024 August | 11 | 5 | 16 |
| 2024 July | 9 | 1 | 10 |
| 2024 June | 12 | 3 | 15 |
| 2024 May | 8 | 2 | 10 |
| 2024 April | 11 | 7 | 18 |
| 2024 March | 15 | 3 | 18 |
| 2024 February | 12 | 3 | 15 |
| 2024 January | 3 | 4 | 7 |
| 2023 December | 10 | 6 | 16 |
| 2023 November | 6 | 7 | 13 |
| 2023 October | 4 | 5 | 9 |
| 2023 September | 8 | 1 | 9 |
| 2023 August | 6 | 1 | 7 |
| 2023 July | 5 | 2 | 7 |
| 2023 June | 7 | 1 | 8 |
| 2023 May | 13 | 3 | 16 |
| 2023 April | 7 | 2 | 9 |
| 2023 March | 6 | 1 | 7 |
| 2023 February | 12 | 1 | 13 |
| 2023 January | 13 | 8 | 21 |
| 2022 December | 17 | 10 | 27 |
| 2022 November | 17 | 7 | 24 |
| 2022 October | 17 | 7 | 24 |
| 2022 September | 8 | 3 | 11 |
| 2022 August | 8 | 10 | 18 |
| 2022 July | 7 | 8 | 15 |
| 2022 June | 5 | 7 | 12 |
| 2022 May | 14 | 6 | 20 |
| 2022 April | 7 | 4 | 11 |
| 2022 March | 9 | 10 | 19 |
| 2022 February | 5 | 3 | 8 |
| 2022 January | 13 | 7 | 20 |
| 2021 December | 4 | 10 | 14 |
| 2021 November | 6 | 5 | 11 |
| 2021 October | 6 | 8 | 14 |
| 2021 September | 5 | 11 | 16 |
| 2021 August | 5 | 2 | 7 |
| 2021 July | 6 | 9 | 15 |
| 2021 June | 10 | 8 | 18 |
| 2021 May | 7 | 6 | 13 |
| 2021 April | 11 | 13 | 24 |
| 2021 March | 11 | 7 | 18 |
| 2021 February | 6 | 7 | 13 |
| 2021 January | 5 | 5 | 10 |
| 2020 December | 5 | 5 | 10 |
| 2020 November | 5 | 5 | 10 |
| 2020 October | 8 | 7 | 15 |
| 2020 September | 11 | 12 | 23 |
| 2020 August | 6 | 1 | 7 |
| 2020 July | 5 | 3 | 8 |
| 2020 June | 5 | 4 | 9 |
| 2020 May | 4 | 9 | 13 |
| 2020 April | 2 | 6 | 8 |
| 2020 March | 3 | 4 | 7 |
| 2020 February | 9 | 6 | 15 |
| 2020 January | 4 | 2 | 6 |
| 2019 December | 6 | 3 | 9 |
| 2019 November | 4 | 5 | 9 |
| 2019 October | 2 | 3 | 5 |
| 2019 September | 1 | 3 | 4 |
| 2019 August | 2 | 3 | 5 |
| 2019 July | 2 | 18 | 20 |
| 2019 June | 8 | 5 | 13 |
| 2019 May | 2 | 6 | 8 |
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