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The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis.

ABSTRACT: The human patatin-like phospholipase domain-containing-3 (PNPLA3) gene rs738409 C>G polymorphism is associated with several types of liver disease. The aim of this meta-analysis was to assess the risk of cirrhosis on the basis of rs738409 allele frequency and genotype. Medline, the Cochrane Library, EMBASE, and Google Scholar were searched for prospective and retrospective studies assessing the effect of the rs738409 polymorphism on liver cirrhosis. Seven studies, involving 2,023 patients with cirrhosis, were included. The G allele was associated with a significantly increased risk of cirrhosis versus the C allele [pooled odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.64-2.12, Z = 9.55, P < 0.001]. Both the GC and GG genotypes were associated with a significantly increased risk of cirrhosis versus the CC genotype (GC vs. CC: pooled OR = 1.73, 95% CI = 1.51-1.98, Z = 7.86, P < 0.001; GG vs. CC: pooled OR = 3.41, 95% CI = 2.77-4.18, Z = 11.65, P < 0.001). There was no evidence of publication bias. Our findings suggest that patients at risk for liver cirrhosis may benefit from PNPLA3 genotyping and thus more intensive monitoring if the rs738409 C>G polymorphism is identified.

SUBMITTER: Shen JH

PROVIDER: S-EPMC4274064 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis.

Shen Jian-Hua JH Li Yi-Ling YL Li Dan D Wang Ning-Ning NN Jing Lei L Huang Yu-Hong YH

Journal of lipid research 20141105 1

The human patatin-like phospholipase domain-containing-3 (PNPLA3) gene rs738409 C>G polymorphism is associated with several types of liver disease. The aim of this meta-analysis was to assess the risk of cirrhosis on the basis of rs738409 allele frequency and genotype. Medline, the Cochrane Library, EMBASE, and Google Scholar were searched for prospective and retrospective studies assessing the effect of the rs738409 polymorphism on liver cirrhosis. Seven studies, involving 2,023 patients with c ...[more]

PMID: 25378656

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Project description:ImportanceAlcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk.ObjectiveTo investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality.Design, setting, and participantsThis prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021.ExposuresSelf-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment.Main outcomes and measuresThe primary outcomes were incident cirrhosis and HCC cases and liver disease-related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models.ResultsA total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease-related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease-related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease-related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease-related mortality in persons with excessive drinking and obesity.Conclusions and relevanceThis study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease-related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.

Project description:Genetic variants of PNPLA3 have been implicated in hepatocellular carcinoma (HCC) susceptibility; however, published findings have been both conflicting and inconclusive. To obtain a more precise estimate of the association of the PNPLA3 rs738409 (C > G) polymorphism with the overall risk of HCC and in patients with cirrhosis, we performed a meta-analysis of nine eligible studies identified through an online search of Ovid, PubMed, EBSCO, the Cochrane Library, the Web of Science, the China National Knowledge Infrastructure, Wanfang, and Chinese Biomedicine databases. The studies comprised 1175 patients with HCC, 876 with cirrhosis, and 3026 healthy controls. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess associations, using fixed-effects models. Etiology subgroup and sensitivity analyses were also performed. Our results showed that rs738409 was associated with overall HCC risk and in patients with cirrhosis in the genetic contrast modes: G vs. C, GG + CG vs. CC, GG vs. CG + GG, and GG vs. CC. Stratification by etiology did not reveal any significant association between this polymorphism and hepatitis C virus (HCV)-related HCC in patients with HCV-related cirrhosis (P > 0.05). However, healthy individuals harboring two copies of the rs738409 G variant had a higher risk of HCC (GG vs. CC: OR = 4.40, 95% CI: 3.28-5.91) than those carrying a single G allele (CG vs. CC: OR = 1.62, 95% CI: 1.34-1.59); these significant association were also present in each subgroup. Furthermore, the association was more pronounced in alcohol vs. HCV-related HCC. The present meta-analysis suggests that the PNPLA3 rs738409 G allele is a risk factor for HCC except in patients with HCV-related cirrhosis, and that two copies of the rs738409 G variant conferred a higher risk for HCC in controls, especially for alcohol-related HCC. Further studies with a larger sample size are needed to ascertain the association in different ethnicities.

Project description:BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. Current studies have shown that PNPLA3 (Patatin-like phospholipase domain containing 3) rs738409 G/C gene polymorphism is associated with adult nonalcoholic fatty liver disease [1, 2].But there is no consensus on the relationship between PNPLA3 rs738409 G/C gene polymorphism and children NAFLD due to differences in population samples. To this end, a meta-analysis of published research is conducted to comprehensively assess the relationship between PNPLA3 gene polymorphism and NAFLD in children. METHODS:We searched MEDLINE, PubMed, EMBASE, and CENTRAL databases from inception to May 2019. Case-control studies assessing the relationship between PNPLA3 rs738409 G/C gene polymorphism with non-alcoholic fatty liver disease in children were selected according to inclusion and exclusion criteria. Random effects model was used to quantify the association between the PNPLA3 rs738409 G/C gene polymorphism and the susceptibility of children's NAFLD. Fixed effects model was used to quantify the relationship between the PNPLA3 rs738409 G/C gene polymorphism and the severity of NAFLD in children. The Stata 12.0 software was employed for data analysis. RESULTS:A total of nine case-control studies were included in this meta-analysis containing data of 1173 children with NAFLD and 1792 healthy controls. Five studies compared NAFLD children and non-NAFLD healthy populations. Statistical analysis showed that PNPLA3 gene polymorphism was significantly associated with children's NAFLD in the allele contrast, dominant, recessive and over dominant models (G vs C,OR = 3.343, 95% CI = 1.524-7.334; GG + GC vs CC,OR = 3.157, 95% CI = 1.446-6.892;GG vs GC + CC,OR = 5.692, 95% CI = 1.941-16.689; GG + CC vs GC,OR = 2.756, 95% CI = 1.729-4.392). Four case-control studies compared Children with nonalcoholic fatty liver (NAFL) and children with nonalcoholic steatohepatitis (NASH). The results showed that the PNPLA3 gene polymorphism was also significantly associated with the severity of NAFLD in children in recessive gene model (GG vs GC + CC,OR = 14.43, 95% CI = 5.985-34.997); The Egger's test revealed no significant publication bias. CONCLUSIONS:Meta-analysis showed that PNPLA3 gene polymorphism was significantly associated with susceptibility and severity of NAFLD in children.

Dataset Information

The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis.

Publications

The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis.

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