Given previous reports of the role of IL10 variants in both HCV therapy and clearance we sought to evaluate the role of genetic variants at this gene and its neighbors. We examined a total of 274 African Americans (91 clearance cases and 183 chronically infected matched controls) and 353 European Americans (108 clearance and 245 chronic). There were seven alleles and eight different genotypes in the IL10 and IL19/IL20 genes that had significant associations with HCV clearance, essentially only in African Americans (p=0.05-0.002). Also, as expected, African Americans had more common haplotypes, one in IL10 and two in the IL19/IL20 region some of which indicated associations with HCV (p=0.05-0.001). Most of these single nucleotide polymorphisms (SNPs) have not been associated with HCV outcome in the past, which opens new avenues for candidate gene testing for this disease. In addition, we confirmed the involvement of IL10 distal promoter haplotypes associated with the level of production and HCV clearance. Therefore, results of this study could have implications for the identification of HCV clearance mechanisms as well as therapy decisions. The paper about our findings of SNPs and haplotypes in the IL10 region associated with HCV clearance has been published in Genes and Immunity. Similar approach was taken for HBV. In our analysis, 42 SNPs in IL10, IL19, IL20, FNBP2, IKBKE, RASSF5, LGTN, DYRK3, MARKAPK2, TOSO, PIGR, FKSG87 and SARG in 105 African Americans (36 chronically infected cases, 69 matched clearance controls), and 248 European Americans (97 chronically infected cases, 151 matched clearance controls) were examined for an association with HBV infection outcome, either chronic or recovered. Three SNP variants in IL10, two SNP variants in IL20, and one IL20 haplotype were significantly associated with different HBV disease outcomes in African Americans (P = .005-.04). One of the SNPs in IL20 deviated significantly from the Hardy-Weinberg expectations in African Americans with a large excess of heterozygotes in chronic HBV-infected cases (P = .0006), which suggests a strong genetic effect. Among European Americans, two SNP variants in IL20, as well as one IL20 haplotype were significantly associated with HBV recovery (P = .01-.04). The paper about our findings of SNPs and haplotypes in the IL10 region associated with HBV clearance is being prepared for submission to Hepatology. Several polymorphisms located close to or within the IL10 gene are associated with different transcription levels and the nearby flanking genes are being examined for their potential impact on disease. The importance of the IL10-5'A polymorphism has been identified by pursuing an approach of examining over 170 candidate genes in patient cohorts to test hypotheses of susceptibility to HIV-1 and progression to AIDS. Individuals with the IL10-5'A polymorphism who have a lower level of IL10 production in peripheral blood mononuclear cells upon stimulation progress to AIDS after about five years of infection, faster than individuals without the promoter variant. Other polymorphisms around and within the IL10 gene have been examined in the laboratory to test the degree of linkage disequilibrium around this gene and the possibility that they may be involved in disease progression. Haplotypes encompassing the IL10 gene and its paralogs are currently being statistically analyzed for their potential impact on HIV susceptibility and AIDS progression. Haplotypes carrying the classic promotor ATA polymorphism is related to rapid progression to AIDS compared to any other haplotypes, whereas ACC haplotypes tend to be associates with relatively slower progression, while GCC haplotypes seem to have little or no effect. We did not find any haplotype associations with HIV progression to AIDS among the African Americans and report only the results among the European Americans.
| Shrestha, Sadeep; Strathdee, Steffanie A; Broman, Karl W et al. (2006) Unknown biological mixtures evaluation using STR analytical quantification. Electrophoresis 27:409-15 |
| Shrestha, Sadeep; Strathdee, Steffanie A; Galai, Noya et al. (2006) Behavioral risk exposure and host genetics of susceptibility to HIV-1 infection. J Infect Dis 193:16-26 |
| Shrestha, Sadeep; Smith, Michael W; Beaty, Terri H et al. (2005) Theory and methodology for utilizing genes as biomarkers to determine potential biological mixtures. Ann Epidemiol 15:29-38 |
