The main finding of the present study is the association between the PNPLA3 148M allele and increased insulin resistance and lower baseline viral load among HCV genotype 2 infected patients. PNPLA3 I148M is the most widely replicated genetic variant associated with increased hepatic steatosis [7–11, 30]. Moreover, PNPLA3 148M allele carriers with HCV infection have been reported to have increased prevalence of steatosis, fibrosis, cirrhosis and hepatocellular carcinoma [18–21]. Recent studies on the PNPLA3 148M allele and glucose metabolism suggest a possible involvement of this allele as a genetic determinant [16, 17].
In this study an association between increased insulin resistance and the PNPLA3 148M allele was observed. This association was specifically present in HCV genotype 2 and it was not observed among HCV genotype 3 infected patients. Steatosis is tightly associated with insulin resistance [31, 32]; however, the causal nature of this association remains to be fully elucidated. Insulin resistance has been commonly thought to be a risk factor for liver fat accumulation [33, 34]. Nevertheless, new evidence suggests that hepatic steatosis might be pathogenically responsible for the development of insulin resistance [16, 32, 35]. The association of PNPLA3 148M allele with HOMA-IR in HCV infected subjects supports the hypothesis that insulin resistance may be interpreted as a consequence rather than a cause of hepatic steatosis. To date the role of the PNPLA3 I148M variant on insulin resistance has been controversial, having some previous studies failed to find this association [8, 13–15]; however our result is consistent with a recent study performed in normoglycaemic subjects from Taiwan  that reports 148M allele carriers having higher HOMA-IR levels. Further studies in larger cohorts are warranted to confirm this result.
Interestingly, we found that lower baseline viral load was associated with the PNPLA3 148M allele in HCV genotype 2 but not in HCV genotype 3 infected patients. This finding is novel , although difficult to interpret. HCV has been shown to exploit lipoprotein assembly and export pathways for the release of virions from infected hepatocytes [36–38]. Since PNPLA3 148M allele has been reported to influence lipid accumulation in the liver , it is possible to hypothesize that PNPLA3 148M allele may impair both viral and lipoprotein release from infected hepatocytes resulting in lower baseline plasma viral load in HCV genotype 2 infection. In the presence of HCV genotype 3 infection, however, the intrahepatic impact of PNPLA3 148M allele on lipid particle production appears to be overridden by viral factors.
An important limitation of the present study is the relative small sample size of the HCV genotype 2 infected patients, as well as relative lower rate of PNPLA3 148M allele carriage in Northern Europeans as compared to previous reports from Southern Europe. In fact, even though steatosis has been widely reported to be associated with PNPLA3 148M allele [7, 18–20], only a non-significant trend towards higher prevalence of steatosis was observed among PNPLA3 148M allele carriers in both HCV genotypes in the present study. However, in the analysis adjusted for confounders, the increased risk of steatosis reached marginal significance in genotype 2 but not 3 infected individuals, despite the threefold larger sample size of the latter group. This is in line with previous data showing an association between the PNPLA3 I148M genotype and steatosis in the HCV genotype 2 but not in the HCV genotype 3 infected subjects [18, 19]. Similarly, the relative small sample size of HCV genotype 2 infected patients in the present study may have contributed to the lack of association of the PNPLA3 148M allele with therapeutic outcome despite its effect on baseline viral load and insulin resistance. It is important to bear in mind that given the small sample size our results should be carefully interpreted due to the possibility of both false positive and negative associations. Therefore, this should be considered as a preliminary report and the results need to be confirmed in larger patient cohorts.