Homozygosity for the patatin‐like phospholipase‐3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease†

Abstract

Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 CfiG polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] 5 3.29, 95% confidence interval [CI] 5 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P 5 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR 5 1.35, 95% CI 5 1.04-1.76), nonalcoholic steatohepatitis (OR 5 1.5, 95% CI 5 1.12-2.04), and fibrosis stage >1 (OR 5 1.5, 95% CI 5 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes. Conclusion: In patients with NAFLD, adiponutrin rs738409 CfiG genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis. (HEPATOLOGY 2010;51:1209-1217 Abbreviations: ALT, alanine aminotransferase; FASL, Fas ligand; FFA, free fatty acid; HDL, high-density lipoprotein; INSR, insulin receptor; LDL, low-density lipoprotein; mRNA, messenger RNA; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase-3; PPARa, peroxisome proliferator-activated receptor-a; qRT-PCR, quantitative real-time polymerase chain reaction; a-SMA, a-smooth muscle actin; SNP, single-nucleotide polymorphism; SREBP1c, steroid regulatory element binding protein 1c.From the

PNPLA3 gene in liver diseases

“…Interestingly, Sookoian et al replicated the findings of Romeo et al [6] in NAFLD and extended the association to histological severity, including nonalcoholic steatohepatitis (NASH), after adjustment for age, sex, BMI, and insulin resistance [11]. Other authors reported similar results and further highlighted the fact that rs738409 [G] was not merely associated with steatosis but also with severe liver damage throughout the NAFLD spectrum [12][13][14]. These findings have been summarized in several meta-analyses [15][16][17][18][19] (Table 1).…”

“…In particular, these complex entities composing the tissue environment might interact and thereby drive cancer/host cross-talk, but the details of this interplay are unclear. However, it is noteworthy that the rs738409[G] variant seems to impact the progression of fibrosis independently of the grade of steatosis [12,27,32,35], and this histological feature has not been clearly associated with the risk of HCC occurrence in prospective cohorts of cirrhotic patients [92]. Mechanistic studies should unravel specific impaired biological pathways explaining the frequently reported associations between rs738409[G] and HCC in patients with ALD or NAFLD.…”

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

“…A full discussion is beyond the scope of this article, but the available liter ature has recently been reviewed elsewhere 98 . To date, non synonymous SNPs in two genes in particu lar, PNPLA3 (encoding patatin like phospholipase domain containing protein 3) and TM6SF2 (encoding transmembrane 6 superfamily member 2), have most consistently been validated as associated with NAFLD in separate large cohorts 99,100 . FIG.…”

PNPLA3 and obesity: a synergistic relationship in NAFLD

“…PNPLA3 is a multi functional enzyme that has both triacylglycerol lipase and acyl glycerol O acyltransferase activity, whereas TM6SF2 is required for hepatic secretion of VLDL. Their respective genetic variants have also been associated with steatohepatitis and fibrosis 3,4 , an effect that is thought to be medi ated by altering the lipotoxic composition of intrahepatic lipids. On this point, it should be noted that the Stender et al 2 non invasively assessed hepatic triglyceride, a neutral lipid that does not trigger hepatic insulin resist ance or immune activation.…”