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PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to therapies of lifestyle modification, dipeptidyl peptidase-4 inhibitors, and bariatric surgery. They exhibit much significant reduction of liver fat content, in concurrence with weigh loss and abolished insulin resistance, as compared to those of C-allele carriers. In contrast, patients bearing PNPLA3 rs738409 C-allele (PNPLA3 148I variant), instead of G-allele, demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention. Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409 related diversities in therapeutic efficacy. Therefore, PNPLA3 rs738409 underlies the response to a variety of treatments, which warrants a personalized, precise medicine in NAFLD on the basis of genotype stratification.

SUBMITTER: Wang JZ

PROVIDER: S-EPMC6107533 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease.

Wang Jin-Zhi JZ Cao Hai-Xia HX Chen Jian-Neng JN Pan Qin Q

World journal of clinical cases 20180801 8

Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to t ...[more]

PMID: 30148144

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Project description:BACKGROUND: In a genome-wide association scan, the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase 3 gene (PNPLA3) was strongly associated with increased liver fat content. We investigated whether this SNP is associated with the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) in the Japanese population. METHODS: SNP rs738409 was genotyped by the Taqman assay in 253 patients with NAFLD (189 with nonalcoholic steatohepatitis [NASH] and 64 with simple steatosis) and 578 control subjects. All patients with NAFLD underwent liver biopsy. Control subjects had no metabolic disorders. For a case-control study, the ?(2)-test (additive model) was performed. Odds ratios (ORs) were adjusted for age, gender, and body mass index (BMI) by using multiple logistic regression analysis with genotypes (additive model), age, gender, and BMI as the independent variables. Multiple linear regression analysis was performed to test the independent effect of risk allele on clinical parameters while considering the effects of other variables (age, gender, and BMI), which were assumed to be independent of the effect of the SNP. RESULTS: The risk allele (G-allele) frequency of rs738409 was 0.44 in the control subjects and 0.60 in patients with NAFLD; this shows a strong association with NAFLD (additive model, P = 9.4 x 10(-10)). The OR (95% confidence interval) adjusted for age, gender, and BMI was 1.73 (1.25-2.38). Multiple linear regression analysis indicated that the G-allele of rs738409 was significantly associated with increases in aspartate transaminase (AST) (P = 0.00013), alanine transaminase (ALT) (P = 9.1 x 10(-6)), and ferritin levels (P = 0.014), and the fibrosis stage (P = 0.011) in the patients with NAFLD, even after adjustment for age, gender, and BMI. The steatosis grade was not associated with rs738409. CONCLUSIONS: We found that in the Japanese population, individuals harboring the G-allele of rs738409 were susceptible to NAFLD, and that rs738409 was associated with plasma levels of ALT, AST, and ferritin, and the histological fibrosis stage. Our study suggests that PNPLA3 may be involved in the progression of fibrosis in NAFLD.

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.

Project description:BackgroundTo investigate the correlation between rs738409 polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (encoding I148m) and genetic susceptibility to nonalcoholic fatty liver disease (NAFLD).MethodsWeb of Science, Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform databases were subjected to study retrieving, from the earliest records to November 2022. International databases were searched using the key words (PNPLA3 gene or PNPLA3 polymorphism or patatin-like phospholipase domain-containing pro-tein3) and (nonalcoholic fatty liver disease or NAFLD or nonalcoholic steatohepatitis) and their possible combination. There was no limitation to language. Ethnicity and country restrictions were not applied. Hardy-Weinberg equilibrium about the genotype frequencies of rs738,409 polymorphism in group of controls was assessed using a chi-square goodness-of-fit test (P > .05). A chi-square-based Q test was applied to assess heterogeneity among studies. The random-effect model (DerSimonian-Laird method) was used when a probability value of P < .10, I2 > 50%. If not, the fixed-effect model (Mantel-Haenszel method) was adopted. The current meta-analysis was done by using STATA 16.0.ResultsTwenty studies are selected for this meta-analysis, which includes totally 3240 patients in the treatment group and 5210 patients in the control group. These studies demonstrated a significant increased association between rs738,409 and NAFLD under 5 models: allelic contrast (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.65-2.37, Pheterogeneity = 0.000, Z = 7.346, P = .000), homozygote comparison (OR = 3.59, 95% CI = 2.56-5.04, Pheterogeneity = 0.000, Z = 7.416, P = .000), heterozygote comparison (OR = 1.93, 95% CI = 1.63-2.30, Pheterogeneity = 0.002, Z = 7.507, P = .000), the dominant allele model (OR = 2.33, 95% CI = 1.89-2.88, Pheterogeneity = 0.000, Z = 7.856, P = .000), and the recessive allele model (OR = 2.56, 95% CI = 1.96-3.35, Pheterogeneity = 0.000, Z = 6.850, P = .000). Subgroup analysis shows that the rs738,409 polymorphism of PNPLA3 gene in Caucasians and those with a sample size of < 300 is significantly associated with the susceptibility to nonalcoholic fatty liver. Sensitivity analysis shows that the results of meta-analysis are stable.ConclusionPNPLA3 rs738,409 may play a significant role in increasing risk of NAFLD.

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PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease.

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PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease.

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