• Does a PNPLA3 Polymorphism Promote Fibrosis Progression in Patients with Hepatitis C?

Does a PNPLA3 Polymorphism Promote Fibrosis Progression in Patients with Hepatitis C?

A single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 gene (PNPLA3) is associated with baseline level of fibrosis and its progression, but not development of hepatocellular carcinoma (HCC), in patients with hepatitis C virus (HCV) infection, researchers report in the February issue of Clinical Gastroenterology and Hepatology.

Most patients with chronic HCV infection develop cirrhosis approximately 25–30 years after becoming infected, although this time period varies greatly among individuals.

If it was possible to identify patients most likely to have rapid progression to cirrhosis, their liver function could be closely monitored, they could receive earlier HCV treatment, and they could undergo surveillance for HCC. Prior studies have identified risk factors for fibrosis progression that include older age, male sex, diabetes, obesity, alcohol use, and family history—indicating a role for genetic factors.

For example, the rs738409 C → G single-nucleotide polymorphism, encoding the Ile148Met amino acid change in the PNPLA3 protein, was previously associated with fibrosis and development of HCC in patients with nonalcoholic steatohepatitis. However, there is controversy over its effects on fibrosis in patients with HCV infection.

Muhammad Ali et al evaluated the association between this SNP in PNPLA3 and fibrosis progression and development of HCC in HCV-infected patients, analyzing data from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial.

Among 937 participants with a known PNPLA3 genotype, 384 (41.0%) had cirrhosis at baseline. Ali et al found the PNPLA3 CG/GG SNP at rs738409 to be significantly associated with the presence of cirrhosis (odds ratio of 1.76) after adjusting for age, sex, diabetes, and race.

Among 493 patients without cirrhosis at baseline who had at least 1 follow-up biopsy, 142 had fibrosis progression. In multivariate analyses, fibrosis progression was associated with obesity (odds ratio of 1.67) and the PNPLA3 CG/GG genotype (odds ratio of 1.70).

The PNPLA3 genotype was not associated with HCC development. Furthermore, when the data from Ali et al were used to update prior results from a meta-analysis, the rs738409 SNP in PNPLA3 was not significantly associated with development of HCC in HCV-infected patients.

Ali et al state that their study is unique in that the HALT-C trial evaluated fibrosis at several time points in a large cohort of patients with HCV, allowing a longitudinal assessment of fibrosis progression.

How might this variant of PNPLA3 promote fibrosis progression? PNPLA3 is believed to facilitate fat accumulation in hepatocytes, potentially by interfering with lipoprotein export and promoting lipogenic activity over lipase activity. The Ile148Met amino acid change might promote this process.

Variants in PNPLA3 do not seem to have a direct effect on HCV infection, so some researchers have questioned their association with degree of fibrosis in patients with HCV and other non-steatosis liver diseases. However, Ali et al explain that additional factors, such as alcohol abuse or metabolic syndrome, might promote the association between PNPLA3 activity and level of fibrosis in patients with HCV infection. In support of their model, the authors found the association between PNPLA3 and fibrosis progression to be stronger in patients with steatosis than without steatosis.

Ali et al propose that it is possible that pathways to fibrosis differ with liver disease etiology. The finding that the PNPLA3 polymorphism is not a significant risk factor for HCC among patients with HCV indicates differences in mechanisms of hepatocarcinogenesis with liver disease etiology.

Studies are needed to characterize the functions of PNPLA3 and its interaction with other genes and factors that contribute to fibrosis progression.

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