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"textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Alcoholic liver disease (ALD) is a complex disease that can present in various histological stages: steatosis, steatohepatitis, fibrosis and cirrhosis. The onset of hepatic steatosis is early and predictable in individuals with moderate-high alcohol consumption. However, only 10–35% of patients with steatosis develop steatohepatitis, and of these 10–20% end up with cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The mechanisms that could explain such a variable progression are unknown, although concordance studies on monozygotic twins suggest that a genetic component explains up to 50% of the variability in the progression of ALD.<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. Basically, 2 types of case-control studies have been used: (a) 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 (b) whole genome association studies that compared the genetic variation of all or a large part of the human genome (thousands of polymorphisms are studied at a time).</p><p id="par0015" class="elsevierStylePara elsevierViewall">The candidate gene association studies in ALD have evaluated genes involved in alcohol metabolism (alcohol dehydrogenase, aldehyde dehydrogenase, cytochrome P450 2E1), oxidative stress (glutamate-cysteine ligase, superoxide dismutase), lipid metabolism (MBOAT7) and the immune response (IL10, IL1B, CTLA4). Overall, the results of these studies have been disappointing because, although significant associations were found between particular polymorphisms and the development of cirrhosis, many of these results have not been replicated.<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, inadequate selection of the candidate gene and the presence of confounding factors in the observational studies. There is also a publication bias that has favored the dissemination of studies with significant associations but not those studies with negative results.<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.<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.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Alcohol and its metabolites increase intestinal patency and serum concentrations of bacterial lipopolysaccharide. This effect causes the inflammatory condition that is observed in patients with ALD. Accordingly, several candidate gene association studies have focused on studying the genes involved in the inflammatory response, although most of the findings were not able to be confirmed in subsequent whole genome association studies.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">MicroRNA (miRNA) are small noncoding RNA molecules of 19–23 nucleotides that can modulate messenger RNA concentrations by modifying their transcription and regulating post-transcriptional processes.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Two of these miRNAs (miR-155 and miR-21) have been correlated in ALD to an increased production of TNF-alpha by Kupffer cells in response to the presence of lipopolysaccharide. Similarly, in patients with steatohepatitis, a relationship was found between miR-122 concentrations and alanine aminotransferase readings.<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, cytokine receptors and nuclear factors involved in the immune response.<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.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In this issue of Revista Clínica Española, Novo-Veleiro et al.<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 (IL-12B, IL-16, NFKB1 and IL-1 receptor type 1) involved in the immune response to the lipopolysaccharide and the development of hepatic lesions in ALD. The study by Novo-Veleiro et al. is the first to analyze polymorphisms chosen for their relationship with miRNA that have shown their association with inflammation or hepatic damage in ALD. The other strengths of the study by Novo-Veleiro et al. include the high number of analyzed patients and the incorporation of 2 controls for each case, consisting of healthy volunteers and individuals who abuse alcohol but have not developed liver disease. 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.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Lastly, the study has not shown the association between the polymorphisms of genes that encode inflammatory cytokines and the development of liver injury. Although the proportion of T allele carriers of one of the studied polymorphisms (rs3917328) is lower in the patients with alcoholism than in the healthy volunteers, the multivariate analysis adjusted for confounding factors ruled out this association. It should not surprise us that a study with these characteristics would conclude with negative results. As previously indicated, the reasons could be varied. However, the publication of these results by Revista Clínica Española is important, both for the new methodology in selecting the polymorphisms and by the publication of results with considerable statistical validity. 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.</p></span>"
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