Genome-wide and candidate gene association studies have identified several variants that predispose indi- viduals to developing nonalcoholic fatty liver disease （NAFLD）. However, the gene that has been consis- tentl...Genome-wide and candidate gene association studies have identified several variants that predispose indi- viduals to developing nonalcoholic fatty liver disease （NAFLD）. However, the gene that has been consis- tently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain contain- ing 3 （PNPLA3, also known as adiponutrin）. A nonsyn- onymous single nucleotide polymorphism in PNPLA3 （rs738409 C/G, a coding variant that encodes an amino acid substitution I148M） is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the I148M variant in lipogen- esis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3＇ UTR region （hsa-miR-769-3p and hsa-miR-516a-3p）. In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, cor- roborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol- 3-phosphate acyltransferase 2 is suggested by data miming.展开更多
AIM To examine the association of PNPLA3 polymorphisms in chronic hepatitis C patients and development of liver disease spectrum. METHODS Literature was searched systematically from Pub Med/MEDLINE, EMBASE, and Cochra...AIM To examine the association of PNPLA3 polymorphisms in chronic hepatitis C patients and development of liver disease spectrum. METHODS Literature was searched systematically from Pub Med/MEDLINE, EMBASE, and Cochrane search engines for full-length articles written in English that examined PNPLA3 polymorphism in chronic hepatitis C(CHC) patients. Studies evaluating the association of PNPLA3 polymorphism spectrum(fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) of CHC were included. Pooled data are reported as OR with 95%CI. Our study endpoint was the risk of the entire liver disease spectrum including: Steatosis/fatty liver, cirrhosis, and hepatocellular carcinoma in CHC patients with PNPLA3 polymorphisms.RESULTS Of 380 studies identified, a total of 53 studies were included for full-text review. Nineteen on chronic he-patitis C were eligible for analysis. Pooled ORs for rs738409 GG compared to CC and CG among patients with fatty liver was 2.214(95%CI: 1.719-2.853). ORs among advanced fibrosis/cirrhosis were 1.762(95%CI: 1.258-2.468). Similar odds ratios among hepatocellular carcinoma patients were 2.002(95%CI: 1.519-2.639). Pooled ORs for rs738409 GG and CG compared to CC among patients with fatty liver were 1.750(95%CI: 1.542-1.986). Pooled ORs for advanced fibrosis/cirrhosis patients were 1.613(95%CI: 1.211-2.147). All analyses were homogenous and without publication bias except one. The associations were maintained after adjusting for publication bias and heterogeneity. CONCLUSION PNPLA3 polymorphisms have strong association with increased risk and severity of the liver disease spectrum in CHC patients.展开更多
Background and Aims:Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD).We performed a systematic review and meta-analysis...Background and Aims:Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD).We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease.Methods:Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver,steatohepatitis,cirrhosis,and hepatocellular carcinoma) and NAFLD were included.Pooled data are reported as odds ratios (ORs) with 95% confidence intervals.Results:Of 393 potentially relevant studies,35 on NAFLD were included in the analysis.Compared to healthy controls,the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL)were 1.46 (1.16-1.85) and 2.76 (2.30-3.13),and were 1.75 (1.24-2.46) and 4.44 (2.92-6.76) among patients with non-alcoholic steatohepatitis respectively.The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90-6.13) and 5.05 (1.47-17.29) when comparing nonalcoholic hepatocellular carcinoma to NAFL patients.Among the NAFLD patients,the ORs for G allele frequency when comparing steatosis grade 2-3 to grade 0-1 NAFL,when comparing the NAFLD activity score of ≥ 4 to score ≤ 3,when comparing NASH to NAFLD,when comparing the presence of lobular inflammation to absence,and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43-3.80),1.80 (1.36-2.37),1.66 (1.42-1.94),1.58 (1.19-2.10),and 2.63 (1.87-3.69) respectively.Subgroup analysis based on ethnicity showed similar results.Conclusions:PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs.PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD.展开更多
基金Supported by Grants PICT 2008-1521 and PICT 2010 0441,from National Agency for Science and TechnologyUBACYT CM04,from Universidad de Buenos AiresSookoian S and Pirola CJ belong to National Council of Scientific and Technical Research
文摘Genome-wide and candidate gene association studies have identified several variants that predispose indi- viduals to developing nonalcoholic fatty liver disease （NAFLD）. However, the gene that has been consis- tently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain contain- ing 3 （PNPLA3, also known as adiponutrin）. A nonsyn- onymous single nucleotide polymorphism in PNPLA3 （rs738409 C/G, a coding variant that encodes an amino acid substitution I148M） is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the I148M variant in lipogen- esis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3＇ UTR region （hsa-miR-769-3p and hsa-miR-516a-3p）. In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, cor- roborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol- 3-phosphate acyltransferase 2 is suggested by data miming.
文摘AIM To examine the association of PNPLA3 polymorphisms in chronic hepatitis C patients and development of liver disease spectrum. METHODS Literature was searched systematically from Pub Med/MEDLINE, EMBASE, and Cochrane search engines for full-length articles written in English that examined PNPLA3 polymorphism in chronic hepatitis C(CHC) patients. Studies evaluating the association of PNPLA3 polymorphism spectrum(fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) of CHC were included. Pooled data are reported as OR with 95%CI. Our study endpoint was the risk of the entire liver disease spectrum including: Steatosis/fatty liver, cirrhosis, and hepatocellular carcinoma in CHC patients with PNPLA3 polymorphisms.RESULTS Of 380 studies identified, a total of 53 studies were included for full-text review. Nineteen on chronic he-patitis C were eligible for analysis. Pooled ORs for rs738409 GG compared to CC and CG among patients with fatty liver was 2.214(95%CI: 1.719-2.853). ORs among advanced fibrosis/cirrhosis were 1.762(95%CI: 1.258-2.468). Similar odds ratios among hepatocellular carcinoma patients were 2.002(95%CI: 1.519-2.639). Pooled ORs for rs738409 GG and CG compared to CC among patients with fatty liver were 1.750(95%CI: 1.542-1.986). Pooled ORs for advanced fibrosis/cirrhosis patients were 1.613(95%CI: 1.211-2.147). All analyses were homogenous and without publication bias except one. The associations were maintained after adjusting for publication bias and heterogeneity. CONCLUSION PNPLA3 polymorphisms have strong association with increased risk and severity of the liver disease spectrum in CHC patients.
文摘Background and Aims:Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD).We performed a systematic review and meta-analysis to examine the association of PNPLA3 polymorphisms with the spectrum and severity of this disease.Methods:Studies evaluating the association between the PNPLA3 polymorphism spectrum (fatty liver,steatohepatitis,cirrhosis,and hepatocellular carcinoma) and NAFLD were included.Pooled data are reported as odds ratios (ORs) with 95% confidence intervals.Results:Of 393 potentially relevant studies,35 on NAFLD were included in the analysis.Compared to healthy controls,the pooled ORs for rs738409 CG and GG compared to CC among patients with non-alcoholic fatty liver (NAFL)were 1.46 (1.16-1.85) and 2.76 (2.30-3.13),and were 1.75 (1.24-2.46) and 4.44 (2.92-6.76) among patients with non-alcoholic steatohepatitis respectively.The respective ORs for CG and GG compared to the CC genotype were 2.35 (0.90-6.13) and 5.05 (1.47-17.29) when comparing nonalcoholic hepatocellular carcinoma to NAFL patients.Among the NAFLD patients,the ORs for G allele frequency when comparing steatosis grade 2-3 to grade 0-1 NAFL,when comparing the NAFLD activity score of ≥ 4 to score ≤ 3,when comparing NASH to NAFLD,when comparing the presence of lobular inflammation to absence,and when comparing the presence of hepatocyte ballooning to absence were 2.33 (1.43-3.80),1.80 (1.36-2.37),1.66 (1.42-1.94),1.58 (1.19-2.10),and 2.63 (1.87-3.69) respectively.Subgroup analysis based on ethnicity showed similar results.Conclusions:PNPLA3 polymorphisms have strong association with the risk for and severity of NAFLDs.PNPLA3 polymorphism plays an evolving role in diagnosis and treatment decisions in patients with NAFLD.
