Interleukin 10 polymorphisms as predictors of sustained response in antiviral therapy for chronic hepatitis C infection

Abstract

Host genetic factors have been reported to influence the natural history of hepatitis C virus (HCV) infection. We examined whether variation in interleukin 10 (IL-10) and tumor necrosis factor ␣ (TNF-␣) genes would predict the likelihood of sustained response to antiviral therapy. Single nucleotide polymorphisms (SNPs) and microsatellites at two loci encoding the cytokines IL-10 and TNF-␣ were determined by polymerase chain reaction (PCR)-based techniques. Their relationship to the outcome of antiviral therapy for chronic HCV infection was studied in 49 white patients who had a virologically sustained response (SR) and in 55 white nonresponders (NR) to a combination of interferon alfa-2b and ribavirin (IFN ؉ R). Several IL-10 variants were more frequent among SRs compared with NRs. Carriage of the ؊592A or the ؊819T SNP was associated with SR (odds ratio [OR] ‫؍‬ 2.2; P ‫؍‬ .016). The ؊592A/A and the exclusively linked ؊819T/T genotypes were also associated with SR (OR ‫؍‬ 16.6; P ‫؍‬ .013 for either). The haplotype consisting of the 108-bp IL-10.R microsatellite and ؊3575T, ؊2763C, ؊1082A, ؊819T, ؊592A was also associated with SR (OR ‫؍‬ 2.65; P ‫؍‬ .01). Stratification for viral genotype, baseline viral RNA concentration, and histologic status identified homozygosity for the haplotype as the principal determinant: all 5 homozygous individuals achieved SR (OR crude ‫؍‬ 13.7; P ‫؍‬ .025; stratified ORs ‫؍‬ 1.9-7.0), whereas heterozygotes differed only slightly from wild-type carriers. In contrast, TNF alleles defined by promoter sequences ؊238G/A and ؊308G/A were approximately equally distributed among SR and NR. In conclusion, homozygosity for ؊592A, ؊819T or the extended haplotype (108bp) ؊ ( During the last decade, treatment for hepatitis C virus (HCV) infection has rapidly improved. Interferon alfa-2b in combination with ribavirin (IFN ϩ R) has become the standard regimen for HCV infection. Sustained response (SR) to IFN ϩ R, defined as undetectable HCV RNA at 6 months after discontinuation of therapy, is achievable in 30% to 60% of treated patients.

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

“…There were two haplotypes in the IL19/IL20 region in African Americans significantly associated with HCV clearance, the depleted CTGAAC (OR ¼ 0.56-0.59, P ¼ 0.05-0.04) and the enriched TCAGGC (OR ¼ 1.93-2.7, P ¼ 0.01-0.002). In addition, as a test of association of extended haplotypes in the promoter region with HCV, [38][39][40][41] we analyzed the association of well-studied proximal 46 and distal haplotypes 45 and HCV clearance (Table 4). These results indicated that distal haplotypes AAA (OR ¼ 0.38, P ¼ 0.002-0.003), and TGC (OR ¼ 1.52, P ¼ 0.04-0.03), but not proximal haplotypes in IL10 are associated with clearance of HCV in the AfricanAmerican population.…”

“…36 The commercial IFN-a preparations that are largely used for HCV therapy consist of IFN-a2a or IFN-a2b subtypes. 37 Some of these studies indicate that there is a positive IL10 association with susceptibility to chronic hepatitis C infection and resistance to combined antiviral therapy [38][39][40][41] and rapid fibrosis 39 while in others the association between IL10 promoter region SNPs and viral clearance or persistent infection or severity of disease was not found. [42][43][44] These results further indicated the importance of evaluating HCV clearance in a large set of patients for IL10, its neighboring paralogs, and other genes in the region.…”

Pharmacogenomic perspectives of chronic hepatitis C virus (HCV) infection

“…Pharmacogenetic studies should be useful in elucidating such individual and ethnic disparities in response to HCV therapy. 6,7 The main expectation is that recognition of reliable genetic markers will substantially improve intervention strategies through individualization of therapeutic regimens, thereby reducing costs and avoiding debilitating complications. These studies also hold the promise of identifying additional molecular mechanisms that can be targeted for new, more effective interventions.…”

“…In those analyses of more than a single SNP or mutation in more than 100 patients, preliminary genetic markers include HLA and related variants on chromosome 6, 12,13 homozygosity for an extended haplotype (HHE) along the CCR2 to CCR5 loci on chromosome 3, 14 as well as cytokine gene and related polymorphisms mapped to various locations. [6][7][8] For example, HLA-DRB1*07 was associated with the NR phenotype in treated French (n ¼ 170), 12 while Japanese patients (n ¼ 175) with the LMP7 variant that changes amino acid 49Gln to 49Lys were more likely to be sustained responders (SRs). 13 In CTLA4, the 49G variant on the (À381)C-49G haplotype has been associated with SR in one study of European Americans (n ¼ 158).…”

“…13 In CTLA4, the 49G variant on the (À381)C-49G haplotype has been associated with SR in one study of European Americans (n ¼ 158). 15 For genotypes resolved by similar techniques in multiple studies, inconsistent results have been reported: the IL10 haplotype ATA (i.e., À1082A, À819 T, and À592A) was initially associated with SR status in European Americans (n ¼ 104), 6 but later work suggested that homozygosity of the reciprocal IL10 haplotype GCC (À1082G, À819C, and À592C) had the same effect in a British cohort (n ¼ 319). 7 Although inconsistent findings may reflect differences in ethnic composition and other characteristics of patient populations, small sample sizes appear most problematic in the analyses of stratified patient groups (e.g., NR vs SR).…”