Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis (original) (raw)
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Genetic background in nonalcoholic fatty liver disease: A comprehensive review
World Journal of Gastroenterology, 2015
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide interindividual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous casecontrol studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
Hepatology, 2010
Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 CfiG polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] 5 3.29, 95% confidence interval [CI] 5 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P 5 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR 5 1.35, 95% CI 5 1.04-1.76), nonalcoholic steatohepatitis (OR 5 1.5, 95% CI 5 1.12-2.04), and fibrosis stage >1 (OR 5 1.5, 95% CI 5 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes. Conclusion: In patients with NAFLD, adiponutrin rs738409 CfiG genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis. (HEPATOLOGY 2010;51:1209-1217 Abbreviations: ALT, alanine aminotransferase; FASL, Fas ligand; FFA, free fatty acid; HDL, high-density lipoprotein; INSR, insulin receptor; LDL, low-density lipoprotein; mRNA, messenger RNA; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase-3; PPARa, peroxisome proliferator-activated receptor-a; qRT-PCR, quantitative real-time polymerase chain reaction; a-SMA, a-smooth muscle actin; SNP, single-nucleotide polymorphism; SREBP1c, steroid regulatory element binding protein 1c.
European journal of internal medicine, 2014
Non-alcoholic fatty liver disease was traditionally interpreted as a condition which may progress to liver-related complications. However, the increased mortality is primarily a result of cardiovascular diseases. It has been suggested that fatty liver can be considered as the hepatic consequence of the metabolic syndrome. The aim was to describe the different clinical presentations of non-alcoholic fatty liver disease on the basis of the patatin-like phospholipase domain-containing protein3 (PNPLA3) rs738409 gene variant. Fatty liver was defined by ultrasonographic Hamaguchi's criteria in 211 consecutive subjects with non-alcoholic fatty liver disease. The rs738409 polymorphism was determined by TaqMan assays. Metabolic syndrome was defined according to ATPIII modified criteria. Prevalence of PNPLA3-148II, PNPLA3-148IM, and PNPLA3-148MM genotypes was 45.0%, 40.7%, and 14.3% respectively. Prevalence of metabolic syndrome progressively increased with the severity of liver steatosi...
Genetic Factors Involved in the Development and Progression of Nonalcoholic Fatty Liver Disease
Current Health Sciences Journal, 2015
Purpose. The aim of our study was to identify the possible involvement of adiponutrine polymorphysm and of human leukocyte antigens (HLA) in the development of non-alcoholic fatty liver disease (NAFLD). Material and Methods. We included in this study a total of 138 subjects with non-invasive diagnosis of non-alcoholic hepatic steatosis. The patatin-like phospholipase domain containing protein 3 (PNPLA3) rs738409 (adiponutrine) polymorphism was genotyped by allelic discrimination TaqMan PCR assay (5' nuclease assay), using predesigned TaqMan SNP Genotyping Assays. Class I and II HLA antigens were determined by the polymerase chain reaction sequence specific oligonucleotide method (ADN-PCR-SSO). The results were compared with the same data from the control group subjects. Results. For PNPLA 3 polymorphism we found [CC] genotype in 82 subjects (59,42%), [GC] genotype in 45 (32,61%) and [GG] genotype in 11 subjects (7,97%). The frequency of minor [G] risk allele was 0.25. We found c...
Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease
Nature Genetics, 2008
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations (n = 9,229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 × 10 −10 ) and with hepatic inflammation (P = 3.7 × 10 −4 ). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
PNPLA3 I148M Polymorphism in Patients with Nonalcoholic Fatty Liver Disease, Obesity and Prediabetes
Journal of Gastrointestinal and Liver Diseases
Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance, and therefore predisposes to type 2 diabetes and cardiovascular diseases. Lipid deposition in the liver seems to be critical in the pathogenesis of NAFLD. A common genetic variant, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been associated with NAFLD. The aim of the present study was to evaluate the association between PNPLA3, key gene of lipid metabolism and the metabolic traits in obesity NAFLD patients with and without prediabetes. Methods: A total of 208 obese NAFLD patients without (n=125) and with prediabetes (n=83) were included. The genotyping of PNPLA3 I148M variant (rs738409) was performed by restriction analysis. Results: Regarding rs738409 (I148M) polymorphism, CG genotype was positively correlated with prediabetes, insulin resistance, dyslipidemia and metabolic syndrome compared to the wild CC genotype. The carriers of the...