Human genetics ability to predict the risk of suffering an infectious disease

Moreno Mayordomo, Raquel; López Ramos, Irene; Ortiz de Lejarazu Leonardo, Raúl
doi:10.1016/j.medcle.2017.03.015
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The discovery of the genetic code and the subsequent development of molecular biology have led to a paradigm shift to understand biology&#44; and thus&#44; the concepts of health and disease have evolved&#46; The revolution caused by the development of the Human Genome Project&#44; and its completion in 2005 with the publication on humans&#8217; genetic code opened the door to new fields of research that relate the genetic endowment of every individual with different clinical characteristics&#46; One of these characteristics is the way to deal with an infectious disease&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">An infection involves the entry and multiplication of a microorganism in the tissues of a host&#44; causing a response by the host&#46; In an infectious disease&#44; this response is very important and depends on several factors&#44; including the microbial genome&#44; ultimately responsible for the phenotypic expression of the pathogenic traits of the microorganism&#44; environmental factors and the characteristics inherent to the human subject&#44; codified in their genome&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Throughout history this last factor has been considered less significant&#44; but today it poses a great challenge for genomic medicine&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">It is frequent to genotype microorganisms to know their phylogenetic relationships&#44; to perform a more reliable taxonomic identification or to determine their resistance to antibiotics and chemotherapeutics&#46; However&#44; how is human genetics involved in the susceptibility to infections&#44; clinical evolution or response to their treatment&#63; This is a very complex field and currently under development&#44; since human response to common infections is usually due to a highly polygenic inheritance&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Despite this&#44; their research and study seems important&#44; since infectious diseases are responsible for nearly 30&#37; of deaths worldwide<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> and there are many examples of interindividual variability in responses to these diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The suspected existence of a genetic component in the susceptibility to infections is not so recent&#46; Robert Koch&#44; before discovering the tubercle bacillus in 1882&#44; when he noticed the disease in several members of the same family&#44; suspected it might be a genetic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> However&#44; the discovery of <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> and its association with tuberculosis made the potential genetic hypothesis to be forgotten&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Natural selection exerted by infectious diseases</span><p id="par0025" class="elsevierStylePara elsevierViewall">Throughout the twentieth century&#44; in the study of the clinical course of infections&#44; the human genetic factor regained importance&#46; On the one hand&#44; identical responses were observed against the same infection in twins&#44; in contrast to the high variability existing in the general population to the same clinical case&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> On the other hand&#44; the development of Darwinian evolution theory also shed light on this&#46; The natural selection exerted by pathogenic microorganisms from the dawn of evolution to date has made infectious microorganisms main cause of disease and death throughout human history&#44; not as deadly as when introduced for the first time in a community&#46; This phenomenon became clear during the Spanish and Anglo-Saxon colonization of the Americas&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> since the arrival of colonists&#44; merchant maritime traffic and the opening to the Old World had dramatic consequences on native American Indians&#46; The introduction of infectious diseases from the European continent into populations that had never been in contact with their causal agents caused more deaths than the armed conflicts&#46; Smallpox&#44; influenza&#44; measles&#44; rubella&#44; and tuberculosis were&#44; among others&#44; diseases exported to the American empires&#44; causing a significant natural selection on their populations&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Something similar occurs in West Africa&#44; where important clinical&#44; physiological and immunological differences between ethnic groups have been reported regarding infection&#44; morbidity and prevalence rates of the various plasmodium species&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> The coexistence of Africans with disease from the earliest hominids to date has eased the selection of genetic traits that confer resistance to the disease<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a>&#58; sickle cell anemia&#44; thalassemia&#44; glucose-6-phosphate dehydrogenase deficiency or loss of Duffy erythrocyte antigen &#40;necessary for the invasion of <span class="elsevierStyleItalic">Plasmodium vivax</span>&#41;&#44; among others&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">There are many other examples of natural selection in humans by infectious microorganisms&#44; some of them relatively recent&#46; For example&#44; in the L&#252;beck disaster in 1929&#44; 69&#37; of 251 German children vaccinated with a batch of <span class="elsevierStyleItalic">Calmette-Gu&#233;rin</span> bacillus contaminated with <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#44; survived tuberculosis infection and 9&#37; of them never had a single symptom&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> However&#44; the tubercle bacillus was highly lethal on Native American Indians who were exposed to the bacteria for the first time in the mid-twentieth century&#44; which is estimated to be 90&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> It is clear that the microorganism is a determining factor&#44; but alone it does not explain so many differences in susceptibility between both groups&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Genetic susceptibility to infectious diseases</span><p id="par0040" class="elsevierStylePara elsevierViewall">There are situations where the link between human genetics and susceptibility to infection has been clearly demonstrated&#46; An example is primary immunodeficiencies&#44; conditions where abnormalities in a single gene increase the likelihood of multiple infections&#46; Proof of these are the mutations in ATM and ADA genes&#44; causing ataxia telangiectasia and severe congenital immunodeficiency&#44; respectively in their carriers&#46; It is also known that some variants in the genes encoding the HLA system or cellular mediators such as TNF-&#945;&#44; IFN-&#947; and interleukins increase the risk of serious infection&#44; since the mechanisms of immune response of the organism are damaged4&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> However&#44; linking a particular infectious disease to a particular gene is a much more arduous and&#44; for the moment&#44; impractical task&#44; given the high number of genes normally involved in susceptibility&#46; This causes a significant difficulty in discerning between genetic risk and environmental risk&#44; becoming one of the current challenges in biomedical research&#46; In spite of this&#44; in the last years variants have been found in main genes of susceptibility to many common infections&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">One of the best known examples is the &#916;32 variant of the gene encoding the CCR5 receptor&#44; used by the human immunodeficiency virus &#40;HIV&#41; as a co-receptor for entering lymphocytes and macrophages&#46; Individuals carrying this variant have a nonfunctional CCR5 receptor&#44; to which HIV is unable to bind&#44; resulting in resistance to HIV infection in homozygous carriers and a late progression to acquired immunodeficiency syndrome &#40;AIDS&#41; in heterozygous carriers&#46; Years ago it was proved that an HIV-infected leukemic patient&#44; receiving a bone marrow transplant from a homozygous donor for the CCR5-&#916;32 trait&#44; had undetectable levels of HIV&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a> These findings promoted the development of a new therapeutic strategy in HIV infection&#44; thus synthesizing maraviroc&#44; the first drug used in CCR5 receptor antagonist that blocks the virus entry into the target cell&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Thus&#44; the study of human genetics can help us to better understand the pathophysiology of infections and&#44; therefore&#44; to develop new molecules against new therapeutic targets&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">It has been hypothesized that the &#916;32 variant of CCR5 gene&#44; more prevailing in Caucasians &#40;10&#37;&#41; and practically absent in the rest of the races&#44; might have been favored by natural selection during the smallpox epidemics that decimated Europe during the Middle Ages&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Something similar happens with the Norwalk virus&#44; which causes outbreaks of viral diarrhea&#46; Homozygous individuals with a genetic variant in the &#945;1&#44;2-fucosyltransferase gene &#8211; FUT2 &#8211; do not express the oligosaccharide that acts as a virus ligand&#46; Therefore&#44; they do not develop the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> The same genetic-molecular mechanism has the natural resistance to parvovirus B19&#44; which causes sudden exanthema or fifth disease&#44; since in the absence of the erythrocyte P-antigen by genetic predisposition&#44; the virus cannot enter the cells&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The study of human genetics has occasionally resulted in surprising findings providing evidence of the arbitrariness in Nature&#46; Thus&#44; a lower susceptibility to Ebola hemorrhagic fever has been reported in individuals with Niemann-Pick disease&#44; a rare genetic disease where the NPC1 receptor is mutated&#44; necessary for the entry of the virus into the target cell&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> As above-mentioned for HIV infection&#44; in Ebola virus infection this finding enabled NPC1 receptor antagonist molecules to be tested as potential therapies&#46; The usefulness of these compounds was demonstrated <span class="elsevierStyleItalic">in vitro</span>&#44; since they blocked the entry of Ebola virus into the cells&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> It is likely that in the geographic areas affected by the last Ebola epidemic of 2014&#44; individuals carrying the mutation in NPC1 may have been selected&#44; given the magnitude of the epidemic outbreak and the rarity of the disease&#44; whose estimated prevalence is 1&#58;150&#44;000 people in Western Europe&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> However&#44; further studies are needed in this field to prove this theory&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Usefulness of genome-wide association studies in finding the variants involved in susceptibility</span><p id="par0065" class="elsevierStylePara elsevierViewall">Advances in molecular biology techniques have helped associate common infectious diseases to a major gene through genome-wide association studies &#40;GWAS&#41;&#46; In these tests&#44; the most common genetic variants are studied in different individuals to find out if any of them is associated with any particular trait&#46; GWAS have been typically focused on the study of SNPs &#40;single nucleotide polymorphism&#41;&#44; and their function is to discriminate whether for a certain genetic variant there are different allele frequencies among healthy or non-susceptible and non-healthy individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Two gene variants have been found through GWAS that modify susceptibility to disease by dengue virus in humans&#46; On the one hand&#44; in <span class="elsevierStyleItalic">Fc&#947;RIIa</span>&#44; which encodes for a gammaglobulin receptor used by the virus to enter the cell and also acts as an activator of phagocytic mechanisms&#46; On the other hand&#44; in VDR&#44; which encodes for the vitamin D receptor&#44; which activates the macrophages in charge of phagocytizing viruses&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The different susceptibility of individuals to bacterial infections led the GWAS studies to search for variants in genes that regulate the innate immune response&#46; The results were very varied&#46; We found an association between many variants of the NOD2 gene &#40;involved in cell signaling pathways&#41; and the predisposition to <span class="elsevierStyleItalic">Mycobacterium leprae</span> infection&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> In the case of meningococcal disease&#44; a variant of the gene encoding for complement factor H was associated with protection against the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> And in invasive pneumococcal infection&#44; susceptibility of individuals was found to be associated with the mannose-binding lectin protein encoded by the MBL gene&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> There are&#44; on the other hand&#44; several genes modulating the bactericidal action of macrophages&#44; whose inactivation results in phagolysosomes incapable of lysis of <span class="elsevierStyleItalic">M&#46; tuberculosis</span>&#46; One of the best known is the SLC11A1 gene&#46; Its abnormalities affect the innate bactericidal function of the reticuloendothelial system&#46; Thus&#44; macrophages act as niches or reservoirs for <span class="elsevierStyleItalic">M&#46; tuberculosis</span> and subjects carrying these genetic disorders become potential best carriers of the tubercle bacillus&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Influence of human genetics on the response to treatment of infections</span><p id="par0080" class="elsevierStylePara elsevierViewall">The study of human genetics allows&#44; in certain infections&#44; to provide a therapeutic profile for the patients or modify the already existing profile&#46; There is evidence to determine the presence of genetic variants that can predict the response to the treatment of infections or its adverse reactions&#46; The rs12979860 polymorphism in the IL28B gene predicted whether treatment-na&#239;ve patients with hepatitis C with moderate liver fibrosis and infected with viral genotypes 1 and 4 would respond to standard pegylated interferon and ribavirin combined therapy&#46; Thus&#44; the homozygous carriers of the C allele responded better to this therapy than the T allele carriers&#44; who required the addition of a protease inhibitor to obtain an effective treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> Fortunately&#44; these therapies are not currently being used due to the emergence of new direct-acting antivirals&#46; On the other hand&#44; the spontaneous clearance of the virus is higher in homozygous C carriers&#44; resulting in the delay or absence of clinical progression to cirrhosis and carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Another example of genetic analysis for therapeutic application is the determination of the HLA-B&#42;5701 variant in HIV-infected individuals&#46; Patients with this variant will be at high risk of being hypersensitive to abacavir antiretroviral&#44; making it impossible to administer such treatment which&#44; in combination with other antiretrovirals&#44; is one of the key therapies in the treatment of the disease&#46; As with HCV and rs12979860 polymorphism&#44; this HLA-B&#42;5701 variant causes a slow and late progression to AIDS in HIV-infected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Influence of human genetics on the progression of infection</span><p id="par0090" class="elsevierStylePara elsevierViewall">The presence of certain human genetic factors may also provide information on the severity or progression of infection&#46; A very striking example is the inactivating mutations of the human EVER-1 and EVER-2 genes&#44; which cause abnormal susceptibility to some human papillomavirus &#40;HPV&#41; genotypes&#44; including HPV5 and HPV8&#46; Such mutations produce impaired cellular immunity&#44; disabling recognition and rejection of HPV antigen-presenting keratinocytes&#46; Thus&#44; Epidermodysplasia verrucciform &#40;known as tree man syndrome&#41; occurs in homozygous patients&#44; a disease consisting of a chronic HPV infection with the emergence of hyperkeratosis and high risk of skin cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">In an environment of continuous interrelation between man and pathogenic microorganisms&#44; it seems important to study the human factors responsible for a higher susceptibility to certain infectious diseases&#46; Although such susceptibility to infections depends on multiple factors&#44; tools are being developed to relate different genetic variants with certain traits that may be related not only to the tendency to suffer from a particular infectious disease&#44; but also to the progression or response to its treatment&#46; Some examples of recent findings of human infection-related genes&#44; both by viruses and by prions&#44; bacteria or parasites&#44; are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">In the new era of evidence-based medicine&#44; we try to predict the potential consequences that the same infection can have on different patients depending on their individual characteristics&#46; Thus&#44; the study of human host&#39;s genetics becomes significant in the study of infectious diseases&#44; added to their etiological diagnosis and providing a beneficial synergy for their understanding&#44; treatment and evolution&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Regarding the title of this article&#44; it is concluded that human genetics can indeed predict the risk of any infectious disease&#46; In certain cases&#44; such as in malaria or HIV&#44; there is already scientific evidence on which genetic variants confer resistance to infection&#46; However&#44; genomics still has decades of research ahead where laboratories will be essential to advance in this field&#46; The line separating the various branches of science&#44; such as genetics&#44; microbiology or immunology&#44; is increasingly narrower&#44; and the collaboration of laboratories in biomedical research is necessary for the progress of medicine&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conflict of interest</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest regarding the contents of this article&#46;</p></span></span>"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        1 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Natural selection exerted by infectious diseases"
        ]
        2 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Genetic susceptibility to infectious diseases"
        ]
        3 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Usefulness of genome-wide association studies in finding the variants involved in susceptibility"
        ]
        4 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Influence of human genetics on the response to treatment of infections"
        ]
        5 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Influence of human genetics on the progression of infection"
        ]
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          "identificador" => "sec0035"
          "titulo" => "Conclusions"
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        7 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conflict of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2017-02-24"
    "fechaAceptado" => "2017-03-14"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Moreno Mayordomo R&#44; L&#243;pez Ramos I&#44; Ortiz de Lejarazu Leonardo R&#46; Capacidad de la gen&#233;tica humana de predecir el riesgo de presentar una enfermedad infecciosa&#46; Med Clin &#40;Barc&#41;&#46; 2017&#59;149&#58;32&#8211;35&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Infectious microorganism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Human gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Implication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">References&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Virus</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Human immunodeficiency virus</td><td class="td" title="table-entry  " align="left" valign="top">CCR5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Resistance to infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">De Silva et Stumpf<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a>&#44; 2004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">HLA-B</td><td class="td" title="table-entry  " align="left" valign="top">Progression of disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Jose et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a>&#44; 2013</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Response to treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hepatitis C virus</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">IL28B</td><td class="td" title="table-entry  " align="left" valign="top">Response to treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tanaka et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a>&#44; 2009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Progression of disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Thomas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a>&#44; 2009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hepatitis B virus</td><td class="td" title="table-entry  " align="left" valign="top">HLA-B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Effectiveness of the vaccine</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Godkin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a>&#44; 2005</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA-DR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA-DQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA-DQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Differences in susceptibility</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Mbarek et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a>&#44; 2011</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA-DP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Human papillomavirus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">EVER-1&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Differences in susceptibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Orth<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a>&#44; 2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ebola</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">NPC1</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Resistance to infection</td><td class="td" title="table-entry  " align="left" valign="top">Carette et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a>&#44; 2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C&#244;t&#233; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a>&#44; 2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Norwalk virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">FUT2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Resistance to infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lindesmith et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a>&#44; 2003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Parvovirus B19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">P1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Resistance to infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Brown et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a>&#44; 1994&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dengue</td><td class="td" title="table-entry  " align="left" valign="top">Fc&#947;RIIa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Progression of disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Fang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a>&#44; 2012</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VDR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Differences in susceptibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Prions</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Creutzfeldt-Jakob&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PRNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Differences in susceptibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Palmer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a>&#44; 1991&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Bacteria</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mycobacterium tuberculosis</span></td><td class="td" title="table-entry  " align="left" valign="top">SLC11A1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Differences in susceptibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Li et al&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a>&#44; 2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TLR1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Differences in susceptibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ocejo-Vinyals et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a>&#44; 2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Mycobacterium leprae</span></td><td class="td" title="table-entry  " align="left" valign="top">NOD2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Differences in susceptibility</td><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Zhang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a>&#44; 2009</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA-DR&#47;DQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TLR1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Streptococcus pneumoniae</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MBL2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Differences in susceptibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Roy et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a>&#44; 2002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neisseria meningitidis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CFH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Differences in susceptibility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Davila et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a>&#44; 2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Parasites</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Plasmodium</span> sp&#46;</td><td class="td" title="table-entry  " align="left" valign="top">G6PDH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Differences in susceptibility</td><td class="td" title="table-entry  " align="left" valign="top">Machado et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a>&#44; 2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HBB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Modiano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a>&#44; 1996&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Plasmodium falciparum</span></td><td class="td" title="table-entry  " align="left" valign="top">SLC4A1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Differences in susceptibility</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Machado et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a>&#44; 2010</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ABO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Plasmodium vivax</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">DARC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Resistance to infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Machado et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a>&#44; 2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Relevant infections whose clinical course is influenced by human genetics&#46;</p>"
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