PNPLA3/adiponutrin genotype is strongly associated with metabolic syndrome components and liver damage in patients with Nonalcoholic Fatty Liver Disease

Background: Inherited factors play a major role in the predisposition to develop nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic insulin resistance syndrome and a leading cause of liver disease. Recently, genomewide association studies identified the I148M single nucleotide polymorphism (SNP) of the phospholipase PNPLA3 expressed in the liver and adipose tissue (also known as adiponutrin) as the principal determinant of liver fat content and ALT levels at population level. However, the function of PNPLA3 is still unknown, and the effect of the I148M SNP on histological liver damage has not been evaluated. Aim: To determine whether the I148M PNPLA3 SNP is associated with liver damage in Italian patients with NAFLD. Methods: 261 patients with complete metabolic and histological characterization, and 179 healthy controls with normal liver enzymes and metabolic parameters. The I148M PNPLA3 SNP was determined by Taqman assay (Applied Biosystems). Liver histology was scored according to Kleiner. Hepatic expression of FasL, proapoptotic molecule induced by NASH and insulin resistance, was evaluated by qRT-PCR in 52 patients. Results: the prevalence of the mutant M148 allele was significantly higher in patients vs. controls (41%II 45%IM 14%MM vs. 66%II 31%IM 3%MM, p<.0001). In patients with NAFLD, despite similar age, sex distribution, and BMI, the M148 allele was associated with dyslipidemia (higher triglycerides, and lower HDL cholesterol), and insulin resistance (insulin, HOMA-R index) in a dose-dependent manner (p<.0001 for each comparison). In addition, the M148 allele was associated with higher ALT (33±23II 45±39IM 69±54MM, p<.0001), but not GGT levels, and higher histological severity of steatosis (24±24%II 30±25%IM 37±27%MM, p=.03). Homozygosity for the M148 allele was associated with significantly higher steatosis grade, necroinflammation, and ballooning (p<.05), and higher prevalence of fibrosis stage > 1 (10.6%II 18.2%IM 32.4%MM, p=.008) and > 2 (4.4%II 6.6%IM 18.9%MM, p=.01), and with significantly higher FasL expression (.8±.7 II, 1±.8 IM, 1.7±1.2 MM, HEPATOLOGY, VOLUME 50, NUMBER 4 (SUPPL) AASLD ABSTRACTS 765A p=.02). The association between the 148MM genotype and fibrosis>1 (OR 2.33 95%CI 1.3-4.1) and fibrosis>2 (OR 3.82 95%CI 1.6-9.4) was independent of age, BMI, and diabetes. Conclusion: the I148M PNPLA3 SNP is strongly associated with metabolic syndrome components and liver damage in patients with NAFLD. PNPLA3 likely plays a pivotal role in the progression of liver damage in NAFLD.