Excerpt
In 2008, in an attempt to identify genetic determinants of liver steatosis, Romeo et al. ran an independent genome-wide association study on 2,121 patients enrolled in the Dallas Heart Study that had hepatic fat content assessed by proton magnetic resonance spectroscopy [
1]. By concentrating just on nonsynonymous sequence variations the authors were able to discover a variation (rs738409 C>G) at position 148 in the patatin-like phospholipase-3 (PNPLA3) gene as the strongest determinant of steatosis in patients. The genetic polymorphism encodes an isoleucine-to-methionine substitution. The PNPLA3 gene encodes a 481 amino acid protein of unknown function that belongs to the patatin-like phospholipase family; the progenitor of this family, patatin, has nonspecific lipid acyl hydrolase activity. Following this breakthrough discovery, several candidate gene studies have demonstrated that the G allele of PNPLA3 single nucleotide polymorphism (SNP) influences liver fat accumulation, is associated with disease severity in adult and pediatric populations with NAFLD, and ultimately increases the risk of NASH [
2‐
5]. These results did not go unnoticed among colleagues working in the hepatitis C virus (HCV) field, as several studies were designed to assess the clinical role of the PNPLA3 polymorphisms in patients with chronic hepatitis C. The reasons for this interest are many fold. First, steatosis is known to negatively impact the natural history of HCV infection as it accelerates progression to cirrhosis [
6,
7]. Second, liver steatosis has been shown to be a negative moderator of treatment outcome to interferon (IFN)-based therapies, with patients showing a fatty liver achieving lower sustained virological response rates across all HCV genotypes [
8]. Third, with respect to the plethora of clinical trials currently investigating future potential anti-HCV drugs, the identification of a further genetic polymorphism able to influence treatment outcome would have an enormous impact in the design of future studies [
9]. Among the first to demonstrate the impact of the PNPLA polymorphism in patients with HCV infection were the studies by Valenti et al. and Trèpo et al. who, by analyzing large cohorts of HCV patients in Europe, almost simultaneously reported the G allele of rs738409 SNP to be associated not only with the presence of histologically determined liver steatosis, but also with the presence of cirrhosis and accelerated fibrosis progression [
10,
11]. Ginanni-Corradini et al. further expanded these findings by reporting an increased rate of hepatocellular carcinoma (HCC) development in patients with the GG genotype of rs738409 in a cohort of 222 HCV patients [
12]. Indeed by multivariate analysis the GG genotype was an independent factor associated with HCC development carrying a 2.23 odds ratio. Taken together these data rather unequivocally correlate the G allele of the PNPLA3 SNP with a worse prognosis of chronic hepatitis C. …
