Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10−10) and with hepatic inflammation (P=3.7×10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…For instance, healthy Indian and Asian men are more prone to develop hepatic steatosis and hepatic insulin resistance than other populations because of specific polymorphisms in the insulin-response element for the apolipoprotein C3 gene (Petersen et al, 2006(Petersen et al, , 2010. Confirming the role of the genome in the pathogenesis of NAFLD, another study revealed that Hispanic adults and children are at high risk for the development of NAFLD due to a missense mutation found in the Patatin-like phospholipase domain-containing protein 3 gene (PNPLA3), which is more present in this ethnic group compared to the general population (Romeo et al, 2008). Interestingly, however, patients with variants of the PNPLA3 gene did not develop insulin resistance, suggesting that in this case NAFLD could be dissociated from insulin resistance (Kantartzis et al, 2009).…”

Variant in PNPLA3 is associated with alcoholic liver disease

“…All common haplotypes containing the rs738409[G] allele were more common among individuals with cirrhosis than in the control group (Supplementary Table 4). The rare variant rs6006460[T] reported by Romeo et al 4 is also rare in our Mestizo population (minor allele frequency = 0.002), so we had no power to detect an effect of this variant. The minor T allele of rs6006460 was observed in both the cirrhosis and control groups.…”

“…Recently, Romeo et al 4 carried out a GWAS of nonsynonymous sequence variations in a population comprising Hispanics, African Americans and European Americans to identify genetic variants contributing to nonalcoholic fatty liver disease. They found strong evidence of association of an allele in PNPLA3 (rs738409: C>G, NP_079501.2:p.I148M) with increased hepatic fat levels (P = 5.9 × 10 −10 ), and the association remained highly signifi cant (P = 7.0 × 10 −14 ) after adjustment for body mass index, diabetes status, ethanol use and genetic ancestry.…”

“…Obesity and diabetes are known risk factors for non alcoholic as well as alcoholic liver disease, and expression of PNPLA3 is correlated with obesity 6 . However, studies associating rs738409 with liver dysfunction have not detected associations with systemic metabolic phenotypes, including obesity, plasma lipid levels or insulin resistance 4,6 . These and other results 7 suggest that rs738409 is an independent risk factor for liver dysfunction.…”

Describing the role of ethnicity in the progression of NAFLD: Easier said than done?

“…Because the frequency of biopsy-proven NASH in Latinos and non-Latino whites was the same (63% versus 62%, no P value), there must be additional risk factors that are more prevalent in Latinos. The authors acknowledged that the PNPLA3 rs738409 polymorphism-more prevalent in Latinos than nonLatino whites 3 -may be such a risk factor but underemphasize its potential importance. Speliotes et al recently showed that the rs738409 G allele showed an independent association with histologic measures of NAFLD but not with metabolic traits.…”