The aim of this project is to identify novel host genes and polymorphisms involved in HIV-1 infection and progression to AIDS through an examination of candidate genes along with a mapping by admixture linkage disequilibrium (MALD) genome scan. The Laboratory of Genomic Diversity (LGD) has samples from over 4,000 individuals with a history of HIV-1 exposure or infection. A high-throughput genotyping laboratory that has assayed numerous candidate gene polymorphisms in thousands of HIV-infected and exposed patients has been developed (see Project #Z01 BC 10270-05 LGD). This extensive genotyping allowed performance of survival and categorical analyses to determine relationships between genotypes and phenotypes, making possible estimates of the relative risks and hazards of genetic polymorphisms that influence HIV-1 infection and disease progression along with Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) progression. 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 the IL10 and two in 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 single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance is currently being submitted to Genes and Immunity. Similar analysis was conducted for 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). Three SNPs were identified as significantly associated with the HBV clearance in African Americans, while only one variant was significant in European Americans (p=0.05-0.001). The analysis is now underway that aims to provide a comprehensive evaluation of the association between haplotypes in IL10 and its neighboring paralogs with HBV clearance versus persistence among infected individuals from multiethnic cohorts while evaluating linkage disequilibrium in the region. 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. A patent application was filed on this discovery and the work has now been published (Shin et al., Proc. Natl. Acad. Sci USA 97:14467-14472, 2000). 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.
| 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 |
