Patatin-Like Phospholipase Domain-Containing 3 I148M Polymorphism, Steatosis, and Liver Damage in Chronic Hepatitis C σ

Abstract

Steatosis has been reported to negatively influence the natural history of chronic hepatitis C (CHC), but controversy remains over its causal role due to the confounding effect of adiposity, insulin resistance, and diabetes. The rs738409 C>G patatin-like phospholipase domain-containing 3 (PNPLA3) single nucleotide polymorphism (SNP), encoding for the I148M protein variant, influences liver fat without affecting insulin resistance and body composition. The aim of this study was to evaluate the effect of the rs738409 CG genotype on liver fat and fibrosis in CHC patients. We also explored the possible effect of PNPLA3 genotype on other steatosis-related complications, namely, treatment failure and hepatocellular carcinoma (HCC) development. To this end we considered two independent series of 325 and 494 CHC patients with available DNA and liver biopsy followed at tertiary referral centers in northern Italy. The rs738409 genotype was determined by a Taqman assay. The rs738409 GG genotype, observed in 10% of patients, was associated with steatosis independently of age, sex, body mass index (BMI), diabetes, alcohol intake, and viral genotype (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.4-2.7; P < 0.001). The association with rs738409 genotype was confirmed for severe steatosis, was independent of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) values, and was observed in all viral genotypes but the 3. The rs738409 GG genotype was associated with fibrosis stage and cirrhosis (OR 1.47, 95% CI 1.2-1.9; P 5 0.002), treatment response (n 5 470; OR 0.63, 95% CI 0.4-0.8; P 5 0.006), and HCC occurrence (n 5 325; OR 2.16, 95% CI 1.3-3.6; P 5 0.002), independently of confounders. Conclusion: The rs738409 PNPLA3 genotype influences steatosis development in CHC and is independently associated with cirrhosis and other steatosis-related clinical outcomes, such as lack of response to antiviral treatment and possibly HCC. (HEPATOLOGY 2011;53:791-799)

PNPLA3 gene in liver diseases

“…Interestingly, the impact of the SNP seems to be lower compared to fatty liver diseases, as indicated by the lower odds-ratios (OR) observed in carriers of rs738409 [G] with histological damage phenotypes in this etiology. Thus, the association between rs738409[G] and liver damage appears to mainly concern patients who are homozygous for the mutant G allele following a recessive model of inheritance (i.e., GG vs. CC + CG genotypes) [32,34,35]. A significant interaction between age at infection and rs738409 [G] has also been reported in one study [37].…”

“…In CHC, a significant association of rs738409 [G] with steatosis [32][33][34][35], and/or fibrosis [32,34,35] was observed in several independent European cohorts following adjustment for other known environmental risk factors. The association with fibrosis has now been confirmed…”

IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

“…Inherited host factors influence fibrogenesis in CHC patients [1], often by interacting with acquired risk factors, as exemplified by the synergic effect of overweight, alcohol, and the PNPLA3 I148M polymorphism in the pathogenesis of steatosis, a major cofactor of liver damage in CHC [2][3][4][5]. Besides conditioning treatment response, viral factors also impact on disease evolution, and again the directly steatogenic HCV genotype-3 has been linked to accelerated fibrosis [6].…”

“…However, it is known that these variants result in a different pattern of activation of the innate immune system against HCV infection, as determined by the different basal and IFN-a induced expression of interferon-stimulated genes and inflammatory activity [21,22]. Favorable IL28B variants, likely through the effect of inflammatory cytokines on lipid metabolism [23], protect against the development of steatosis [24] and possibly steatosis-associated fibrosis progression and increased HCC risk [2,4]. As a result, IL28B variants likely have no major effect on the fibrosis-progression rate in patients with ongoing HCV infection [6], even if evidence is still controversial [25].…”

“…It is tempting to speculate that the protection provided by unfavorable IL28B genotypes against inflammation [24,29] may compensate for the association with the 70Q core variant and explain the lack of influence on HCC, but further studies evaluating prospectively the interaction among genotypes of IL28B, PNPLA3 (associated with steatosis and HCC in CHC [4]), and HCV core mutants are needed to test this hypothesis.…”