Dataset Information

Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis.

ABSTRACT: We conducted a meta-analysis to assess the association between patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) and its subtypes simple steatosis(SS) and nonalcoholic steatohepatitis (NASH). The study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, with assessment for heterogeneity and publication bias. Twenty-three case-control studies involving 6071 NAFLD patients and 10366 controls were identified. The combined results showed a significant association between NAFLD risk and the rs738409 polymorphism in all genetic models (additive model: OR = 3.41, 95% CI = 2.57-4.52; P < 0.00001). In addition, evidence indicated that the rs738409 polymorphism was significantly associated with NASH in all genetic models (additive model: OR = 4.44, 95% CI = 3.39-5.82; P < 0.00001). The subgroup and sensitivity analyses showed that these changes were not influenced by the ethnicities and ages of subjects or by the source of controls. The rs738409 polymorphism was only significantly associated with risk of simple steatosis in the allele contrast and had no effect in the other genetic models. These findings suggest that the rs738409 polymorphism in PNPLA3 gene confers high cross-ethnicity risk for NAFLD and NASH development.

SUBMITTER: Xu R

PROVIDER: S-EPMC4366950 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis.

Xu Renfan R Tao Anyu A Zhang Shasha S Deng Youbin Y Chen Guangzhi G

Scientific reports 20150320

We conducted a meta-analysis to assess the association between patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) and its subtypes simple steatosis(SS) and nonalcoholic steatohepatitis (NASH). The study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, with assessment for heterogeneity and publication bias. Twenty-three case-control studies involving 6 ...[more]

PMID: 25791171

Similar Datasets

Project description:UnlabelledGenome-wide association studies identified single-nucleotide polymorphisms (SNPs) that are associated with increased hepatic fat or elevated liver enzymes, presumably reflecting nonalcoholic fatty liver disease (NAFLD). To investigate whether these SNPs are associated with histological severity of NAFLD, 1117 (894 adults/223 children) individuals enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network and National Institutes of Health Clinical Center studies with histologically confirmed NAFLD were genotyped for six SNPs that are associated with hepatic fat or liver enzymes in genome-wide association studies. In adults, three SNPs on chromosome 22 showed associations with histological parameters of NASH. After adjustment for age, sex, diabetes, and alcohol consumption, the minor allele of rs738409 C/G, a nonsynonymous coding SNP in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) (adiponutrin) gene encoding an Ile148Met change, was associated with steatosis (P = 0.03), portal inflammation (P = 2.5 x 10(-4)), lobular inflammation (P = 0.005), Mallory-Denk bodies (P = 0.015), NAFLD activity score (NAS, P = 0.004), and fibrosis (P = 7.7 x 10(-6)). Two other SNPs in the same region demonstrated similar associations. Three SNPs on chromosome 10 near the CHUK (conserved helix-loop-helix ubiquitous kinase) gene were independently associated with fibrosis (P = 0.010). In children, no SNP was associated with histological severity. However, the rs738409 G allele was associated with younger age at the time of biopsy in multivariate analysis (P = 0.045).ConclusionIn this large cohort of histologically proven NAFLD, we confirm the association of the rs738409 G allele with steatosis and describe its association with histological severity. In pediatric patients, the high-risk rs738409 G allele is associated with an earlier presentation of disease. We also describe a hitherto unknown association between SNPs at a chromosome 10 locus and the severity of NASH fibrosis.

Project description:To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH).We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis.PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ? 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3).The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH.

Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide, with significant morbidity associated with nonalcoholic steatohepatitis (NASH). Genome-wide association studies demonstrated that the variants rs738409 C/G in the PNPLA3 and rs58542926 C/T in the TM6SF2 genes are determinants of inter-individual and ethnicity-related differences in hepatic fat content and NAFLD progression.AimTo investigate PNPLA3 and TM6SF2 genotype frequency and their association with NAFLD development and progression in Brazilian patients.MethodsThis cross-sectional case-control study enrolled 285 individuals from the Gastroenterology and Hepatology clinics at a university hospital in Brazil. The case patients (n = 148) were confirmed to have NAFLD by the identification of hepatic steatosis on ultrasonography and exclusion of other causes of liver disease. According to the clinical protocol, patients underwent liver biopsy when at high risk for NASH and/or advanced fibrosis (n = 65). Steatohepatitis was confirmed in 54 patients. Individuals who did not have biopsy indication or NASH on histology were considered to have simple steatosis (n = 94). The control group (n = 137) was selected among patients that attended the Intestinal Disease clinic and was composed of subjects without abnormalities on abdominal ultrasonography and normal liver biochemical tests. All individuals underwent PNPLA3 and TM6SF2 genotype analysis.ResultsPNPLA3 CC, CG and GG genotype frequencies were 37%, 44% and 19%, respectively, in NAFLD patients and were 58%, 31% and 10% in controls (P < 0.001). In a model adjusted for gender, age, body mass index and type 2 diabetes mellitus, the G allele increased the chance of NAFLD (OR = 1.69, 95%CI: 1.21-2.36, P = 0.002) and NASH (OR = 3.50, 95%CI: 1.84-6.64, P < 0.001). The chance of NASH was even higher with GG homozygosis (OR = 5.53, 95%CI: 2.04-14.92, P = 0.001). No association was found between G allele and the features of metabolic syndrome. In histological assessment, PNPLA3 genotype was not associated with steatosis grade, although GG homozygosis increased the chance of significant NASH activity (OR = 17.11, 95%CI: 1.87-156.25, P = 0.01) and fibrosis (OR = 7.42, 95%CI: 1.55-34.47, P = 0.01) in the same adjusted model. TM6SF2 CC, CT and TT genotype frequencies were 83%, 15% and 0.7%, respectively, in NAFLD patients and were 84%, 16% and 0.7% in controls (P = 0.78). The T allele presence was not associated with NAFLD or NASH, and was not associated with histological features.ConclusionPNPLA3 may be involved in susceptibility and progression of NAFLD and NASH in the Brazilian population. More advanced histological liver disease was associated with the G allele. The TM6SF2 genetic variants were not associated with NAFLD susceptibility and progressive histological forms in the population studied, but further studies are required to confirm these findings.

Dataset Information

Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis.

Publications

Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets