We examined the association between related genes and the efficacy of SOC therapy and identified the GNB1 gene on chromosome 1 as a new candidate susceptibility gene. In this study, we found that the SNPs rs4648727 and rs12126768 in the introns of GNB1 may be associated with the rate of RVR to PEG-IFNα-RBV treatment. In addition, we found that 1 GNB1 haplotype (ACAT), which is a combination of the set of SNPs in this gene, was statistically associated with RVR. Clinical association studies showed that the GNB1 haplotype (ACAT) carriers were significantly associated with a higher archived rate of RVR (OR in the range of 1.81–4.54) in both HCV-1 and HCV-2 infected patients. This finding led us to the hypothesis that the treatment response to PEG-IFNα-RBV could, in part, be dependent on GNB1. The genotypes of GNB1 were equally distributed in males and females, the viral load, age at study entry, BMI, and others clinical data did not differ significantly among the different genotypes in the HCV-1 and HCV-2 infected populations. Therefore, it is unlikely that specific GNB1 genotypes predispose individuals to infection with HCV-1 and HCV-2 or contribute to spontaneous virus elimination.
Several reports have provided strong evidence that patients infected with HCV-1 have about a 50% (in Caucasians) and 80% (in African Americans) probability of a poor response toward PEG-IFNα-RBV treatment. In our study, the overall RVR rates were less than 45% and 85% in the HCV-1 and HCV-2 populations, respectively. Therefore, reliable prediction of a non-viral response in the beginning of treatment would avoid side effects and reduce the cost of treatment. Although, viral clearance has been strongly associated with various clinical features, for example, gender, age <40 years, low HCV RNA level before treatment, absence of liver cirrhosis, and HCV genotype 2/3 . Many researchers are still focused on the identification of host genetic factors that may be related to clinical outcomes and providing custom therapy for HCV infection.
Previous studies have shown that the 825T allele of GNB3 and its associated haplotypes are predictors of enhanced signal transduction via G proteins. The GNB3 825 C/C genotype is associated with non-response in HCV-1 infected patients [17, 26]. Although the heterotrimeric transformation of G proteins is not directly involved in the interferon-signaling pathway, PEG-IFNα-RBV treatment, which may initiate multiple chemokine responses, may involve heptahelical receptors coupled to G proteins . Therefore, polymorphism in genes encoding components of the chemokine system may be related to treatment outcomes. In this study, the exact mechanism by which GNB1 genotypes are associated with decreased or increased G protein activation remains to be determined.
Although several virological responses have been used to predict SVR, on comparing the baseline characteristics, we observed that RVR increased and remained a strong predictor of SVR . In the HCV-1 infected population, the SVR rate were significantly higher in the RVR (+) patients (89.8%) than in the RVR (−) patients (10.2%). On the other hand, in the HCV-2 infected population, the SVR rate was significantly higher in the RVR (+) group (94.3%) than in the RVR (−) group (5.7%). However, we did not find a significant association between GNB1 SNPs and SVR. To estimate the sample sizes for this association test, which would ensure a maximum power of 80% at P < 0.05, we calculated the sample size by using the G*Power 3.1 software. In future studies, we plan to enroll a total of >1000 patients. Therefore, additional factors need to be incorporated to ensure a high likelihood for discriminating the patients with RVR who will achieve SVR from those who will not.
In 2 previous GWAS studies, they concluded that SNPs in or near the IL-28B gene strongly determined the outcome of HCV therapy [19, 28–30]. The most significant SNP in their study groups was rs8099917, which was associated with SVR in European and Japanese patients. Interestingly, rs8099917 was not associated with the response to PEG-IFNα-RBV therapy in HCV-2/3 infected patients. They proposed that, the contributions of host genetic factors to HCV-2/3 clearance are relatively low compared with the contributions of host genetic factors to HCV-1 clearance because HCV-2/3 is more likely to be eliminated by SOC therapy. Our results demonstrated that the GNB1 haplotype (ACAT) was significantly associated with a higher rate of RVR both in HCV-1 and HCV-2 infected populations. The significance of the genetic effect of GNB1 in other ethnicities remains to be elucidated.
Although we did not analyze the functional effects of these intronic SNPs on the G protein, they were associated with SOC therapy outcome. Since the GNB1 gene was weakly associated with therapeutic outcomes, the linkage among these GNB1 polymorphisms and RVR/SVR should be confirmed in future studies with larger enrolled populations. The results of this study may provide novel information toward determining the exact response to PEG-IFNα-RBV.