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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Alcoholic liver disease &#40;ALD&#41; is a complex disease that can present in various histological stages&#58; steatosis&#44; steatohepatitis&#44; fibrosis and cirrhosis&#46; The onset of hepatic steatosis is early and predictable in individuals with moderate-high alcohol consumption&#46; However&#44; only 10&#8211;35&#37; of patients with steatosis develop steatohepatitis&#44; and of these 10&#8211;20&#37; end up with cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The mechanisms that could explain such a variable progression are unknown&#44; although concordance studies on monozygotic twins suggest that a genetic component explains up to 50&#37; of the variability in the progression of ALD&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Numerous studies have attempted to identify the genetic polymorphisms potentially associated with the development of ALD&#46; Basically&#44; 2 types of case-control studies have been used&#58; &#40;a&#41; candidate gene association studies that compared the frequency of the onset of polymorphisms of one or several genes chosen based on previous knowledge of their participation in the disease and &#40;b&#41; whole genome association studies that compared the genetic variation of all or a large part of the human genome &#40;thousands of polymorphisms are studied at a time&#41;&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The candidate gene association studies in ALD have evaluated genes involved in alcohol metabolism &#40;alcohol dehydrogenase&#44; aldehyde dehydrogenase&#44; cytochrome P450 2E1&#41;&#44; oxidative stress &#40;glutamate-cysteine ligase&#44; superoxide dismutase&#41;&#44; lipid metabolism &#40;MBOAT7&#41; and the immune response &#40;IL10&#44; IL1B&#44; CTLA4&#41;&#46; Overall&#44; the results of these studies have been disappointing because&#44; although significant associations were found between particular polymorphisms and the development of cirrhosis&#44; many of these results have not been replicated&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The main reasons for not finding significant associations are a lack of statistical power&#44; inadequate selection of the candidate gene and the presence of confounding factors in the observational studies&#46; There is also a publication bias that has favored the dissemination of studies with significant associations but not those studies with negative results&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Several whole genome association studies on ALD have found significant relationships between polymorphisms of genes PNPLA3 and TM6SF2 and the risk of developing cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> There are studies underway that seek to validate the clinical utility of these polymorphisms for predicting the prognosis and response to treatment&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Alcohol and its metabolites increase intestinal patency and serum concentrations of bacterial lipopolysaccharide&#46; This effect causes the inflammatory condition that is observed in patients with ALD&#46; Accordingly&#44; several candidate gene association studies have focused on studying the genes involved in the inflammatory response&#44; although most of the findings were not able to be confirmed in subsequent whole genome association studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">MicroRNA &#40;miRNA&#41; are small noncoding RNA molecules of 19&#8211;23 nucleotides that can modulate messenger RNA concentrations by modifying their transcription and regulating post-transcriptional processes&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Two of these miRNAs &#40;miR-155 and miR-21&#41; have been correlated in ALD to an increased production of TNF-alpha by Kupffer cells in response to the presence of lipopolysaccharide&#46; Similarly&#44; in patients with steatohepatitis&#44; a relationship was found between miR-122 concentrations and alanine aminotransferase readings&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> These effects of miRNA in ALD are thought to be the result of their capacity to modify the expression of cytokine genes&#44; cytokine receptors and nuclear factors involved in the immune response&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> It has therefore been assumed that these miRNA could serve as markers to identify candidate genes for association studies on ALD&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In this issue of Revista Cl&#237;nica Espa&#241;ola&#44; Novo-Veleiro et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> presents the results of a new association study between a number of cytokine gene polymorphisms &#40;IL-12B&#44; IL-16&#44; NFKB1 and IL-1 receptor type 1&#41; involved in the immune response to the lipopolysaccharide and the development of hepatic lesions in ALD&#46; The study by Novo-Veleiro et al&#46; is the first to analyze polymorphisms chosen for their relationship with miRNA that have shown their association with inflammation or hepatic damage in ALD&#46; The other strengths of the study by Novo-Veleiro et al&#46; include the high number of analyzed patients and the incorporation of 2 controls for each case&#44; consisting of healthy volunteers and individuals who abuse alcohol but have not developed liver disease&#46; The availability of these 2 control groups helps differentiate between the polymorphisms associated with excessive alcohol intake and those related to a poorer progression of the liver disease&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Lastly&#44; the study has not shown the association between the polymorphisms of genes that encode inflammatory cytokines and the development of liver injury&#46; Although the proportion of T allele carriers of one of the studied polymorphisms &#40;rs3917328&#41; is lower in the patients with alcoholism than in the healthy volunteers&#44; the multivariate analysis adjusted for confounding factors ruled out this association&#46; It should not surprise us that a study with these characteristics would conclude with negative results&#46; As previously indicated&#44; the reasons could be varied&#46; However&#44; the publication of these results by Revista Cl&#237;nica Espa&#241;ola is important&#44; both for the new methodology in selecting the polymorphisms and by the publication of results with considerable statistical validity&#46; These findings will be useful in implementing future studies that analyze the relationship between genes that encode the inflammatory response and the development of liver injury in ALD&#46;</p></span>"
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DOI: 10.1016/j.rceng.2018.03.002
Genetic studies and alcoholic liver disease
Los estudios genéticos y la enfermedad hepática alcohólica
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P. Zapatera,b,c
a CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
b Unidad de Farmacología Clínica. Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Alicante, Spain
c Instituto de Bioingeniería. Universidad Miguel Hernández, Elche, Alicante, Spain
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