The PNPLA3 Genetic Variant rs738409 Influences the Progression to Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients

Abstract

Contradictory data about the impact of the rs738409 steatosis-related polymorphism within PNPLA3 gene on liver fibrosis progression in HIV/hepatitis C virus (HIV/HCV)-coinfected patients have been reported. Our objective was to test whether this, and other polymorphisms previously related to fatty liver disease in HIV infection linked to SAMM50 or LPPR4 genes, influence liver fibrosis progression in HIV/HCV-coinfected individuals. Three hundred and thirty two HIV/HCV-coinfected patients who consecutively attended four Spanish university hospitals from November 2011 to July 2013 were included. A liver stiffness cut-off of 14.6 kPa, as determined by transient elastography, was used to diagnose cirrhosis. Liver stiffness progression was studied in 171 individuals who had two available LS determinations without anti-HCV treatment between them. Moreover, 28 HIV/HCV-coinfected patients who underwent liver transplant, as well as 19 non-cirrhotic coinfected individuals used as controls, were included in an additional study. Only rs738409 was associated with cirrhosis: 45 (29.6%) of 152 G allele carriers versus 36 (20.0%) of 180 CC carriers showed cirrhosis (multivariate p = 0.018; adjusted odds ratio = 1.98; 95% confidence interval = 1.12–3.50). Also, 21 (30.4%) of 69 G allele carriers versus 16 (15.7%) of 102 CC patients showed significant liver stiffness progression (adjusted p-value = 0.015; adjusted odds ratio = 2.89; 95% confidence interval = 1.23–6.83). Finally, the proportion of rs738409 G allele carriers was significantly higher in transplanted individuals than in controls (p = 0.044, odds ratio = 3.43; 95% confidence interval = 1.01–11.70). Our results strongly suggest that the rs738409 polymorphism is associated with liver fibrosis progression in HIV/HCV-coinfected patients.

PNPLA3 Gene Polymorphisms in HCV/HIV-Coinfected Individuals

“…15 Furthermore, we did not find any association with advanced fibrosis/cirrhosis which has been noted in other studies. 16 Our findings are in agreement with Scheiner et al, who reported no association between PNPLA3 polymorphisms and fibrosis stage. Similarly, they also reported no clear link between PNPLA3 and effect on virologic response following pegylated interferon/ribavirin therapy.…”

PNPLA3 rs738409 G allele carriers with genotype 1b HCV cirrhosis have lower viral load but develop liver failure at younger age

“…More than fifty studies demonstrating that the PNPLA3 rs738409 G allele is a risk factor for non-alcoholic steatohepatitis (NASH), liver cirrhosis in NASH or alcoholic liver disease have been published in the past decade [5–11]. The same allele was also identified as a risk factor for liver fibrosis and cirrhosis in HCV-monoinfected individuals [12–16] and in those with HCV/HIV coinfection [17–20] and it also turned out to be a predisposing factor of hepatocellular carcinoma (HCC) [21–24]. In a recent study, the increased risk of HCC and PNPLA3 G allele was found only in alcoholic liver disease, but not in non-alcoholic fatty liver disease or viral hepatitis B and C [25].…”

PNPLA3 expression and its impact on the liver: current perspectives

“… 75 In particular, a recent study conducted in a larger population clearly defined the role of I148M PNPLA3 as an independent risk factor for fibrosis progression, resulting in higher cirrhosis occurrence in HIV/HCV co-infected patients. 76 Molecular data have shown that HCV alters dramatically lipid metabolism in infected hepatocytes, 77 suggesting a possible link between I48M PNPLA3 in remodeling LDs and thus favoring fat accumulation leading to steatosis. However, further mechanistic studies are needed to verify this hypothesis.…”