Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease

PNPLA3 gene in liver diseases

“…The authors elegantly demonstrated an allele-dose effect of rs738409[G] from alcoholics without evidence of liver damage compared to ALD patients with elevated ALT without clinical, biological, or imaging signs of cirrhosis, and ultimately alcoholic cirrhotics [25]. This association was subsequently replicated in several independent cohorts, mostly among individuals of European descent [26,27], and summarized in two metaanalyses [28,29] (Table 1). More recently, the first GWAS in ALD comparing 1426 heavy drinkers without liver injury to 712 patients with alcoholic cirrhosis, all of European descent, reported that PNPLA3, TM6SF2, and MBOAT7, three independent loci all involved in lipid metabolism, were significantly associated with a more severe phenotype [30].…”

“…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.…”

Investigation of PNPLA3 and IL28B Genotypes on Diabetes and Obesity After Liver Transplantation: Insight Into Mechanisms of Disease

“…This activity is disrupted or reduced in the variant (G allele) polymorphism (21), which may lead to increased energy (triglyceride) storage in hepatocytes and adipocytes (22). PNPLA-3 G alleles appear strongly associated with steatosis, steatohepatitis and fibrosis progression in alcoholic and nonalcoholic fatty liver disease (15,17) as well as hepatitis C related liver disease (16,23). In this study the G allele frequency appears slightly higher in the liver transplant recipient population (29%) than in the general population ($21% to 25%) (14,18,19,24).…”

“…Patatin-like phospholipase domain-containing 3 (PNPLA-3) gene polymorphisms (rs738409), on chromosome 22 have been linked to fatty liver disease (14,15), worsening fibrosis in alcoholic or hepatitis c related liver disease (16,17), obesity and less clearly with insulin resistance in the general population (14,18,19). The association with advanced liver disease may increase the prevalence of the high risk PNPLA-3 genotype in the transplant population, but has not been assessed.…”

Letter: PNPLA3 and alcoholic liver disease - an alert to methodological limitations. Authors’ reply

“…Second, several publications report to have analysed this polymorphism on the forward strand, [6][7][8] and no study, to the best of our knowledge, specifically reports to have analysed it on the reverse strand.…”