Abstract
Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV) infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on sustained virological response (SVR) to pegylated interferon-α and ribavirin (pegIFN/RBV) treatment of HCV genotypes 1 and 3 infections. We conducted a candidate gene association study in a prospective cohort of 201 chronic HCV-infected individuals undergoing treatment with pegIFN/RBV. Differences between groups were compared in logistic regression adjusted for age, HCV viral load and interleukin 28B genotypes. Four single nucleotide polymorphisms (SNPs) located in the B-cell lymphoma 2-like 1 (BCL2L1) gene were significantly associated with SVR. SVR rates were significantly higher for carriers of the beneficial rs1484994 CC genotypes. In multivariate logistic regression, the rs1484994 SNP combined CC + TC genotypes were associated with a 3.4 higher odds ratio (OR) in SVR for the HCV genotype 3 (p = 0.02). The effect estimate was similar for genotype 1, but the association did not reach statistical significance. In conclusion, anti-apoptotic SNPs in the BCL2L1 gene were predictive of SVR to pegIFN/RBV treatment in HCV genotypes 1 and 3 infected individuals. These SNPs may be used in prediction of SVR, but further studies are needed.
Highlights
Hepatitis C virus (HCV) is a major global health issue, with 170 million individuals chronically infected and 350,000 deaths annually [1].Apoptosis, called programmed cell death, is one of the immune system’s responses to viral infection
For hepatitis C virus (HCV) genotype 1, the sustained virological response (SVR) rates were significantly higher for carriers of the beneficial B-cell lymphoma 2-like 1 (BCL2L1) and interleukin 28B (IL28B) CC genotypes compared to the non-CC genotypes (Table 2)
HCV, hepatitis C virus; SVR, sustained virological response; IL28B, interleukin 28B rs12979860 single-nucleotide polymorphism (SNP); BCL2L1, B-cell lymphoma 2-like 1, rs1484994 single nucleotide polymorphisms (SNPs). * HCV RNA viral load was not measured within 365 days of treatment initiation for 10 individuals
Summary
Hepatitis C virus (HCV) is a major global health issue, with 170 million individuals chronically infected and 350,000 deaths annually [1]. Called programmed cell death, is one of the immune system’s responses to viral infection. Transition pore, which regulates the release of apoptotic regulatory proteins, such as procaspase-9 and cytochrome C [4], to inhibit apoptosis. Both the extrinsic and the intrinsic apoptosis pathways are integrated into a common final pathway resulting in caspase-dependent apoptosis [3]. Glucocorticoid-induced tumour necrosis factor (TNF) receptor-related protein ligand (GITRL) is a newly identified member of the TNF receptor superfamily [5], and its interaction with GITR enhances apoptosis via the intrinsic pathway, possibly through natural killer (NK) cell-induced inhibition of BCL2L1 [6]. We investigated single-nucleotide polymorphisms (SNPs) in the intrinsic apoptosis pathway, hypothesising that they may influence the rates of SVR
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