The recent availability of the human genome sequence and polymorphism databases has revolutionized human population genetics research. We have extracted large numbers of single nucleotide polymorphisms (SNPs) from the database in order to carry out epidemiological studies. Present research is evaluating genetic variation in four clusters of cytokine genes including the IL3, IL4, IL5, IL13 group on chromosome 5; SDF1 on chromosome 10; the MCP1, eotaxin, MCP3, MCP2, MCP4, and I-309 group on chromosome 17; and the MIP1A, PARC, MIP1B, LEC, MPIF1 and RANTES cluster also on chromosome 17. The work has two major aims: 1) Absolute linkage disequilibrium or a reduction in haplotype variation has been identified in many regions of the human genome. This is attributable to either population history or directional selection, or a combination of the two. We are measuring disequilibrium and haplotype diversity in the four cytokine clusters by evaluating variation in SNPs in three ethnic groups: European Americans, African Americans, and Chinese. and 2) Epidemiological association analyses between the SNPs and clinical phenotypes in AIDS, lung cancer and breast cancer cohorts are being conducted. Many of these genes have been implicated in AIDS or cancer pathogenesis using other approaches such as in vitro infection assays, plasma cytokine measurements, cell motility assays, and gene expression tests. Thus far, we have discovered a 31-kb haplotype containing the MCP1, MCP3, and eotaxin chemokine genes that is in absolute linkage disequilibrium in both European Americans and African Americans. This haplotype is associated with resistance to HIV-1 infection in European American homosexuals, suggesting the possible coordinate regulation of these three genes. Measuring plasma chemokine levels in patients with different clinical outcomes is currently being carried out. In addition, a polymorphism changing the last amino acid of the eotaxin signal peptide is associated with susceptibility to infection in European American hemophiliacs. The functional impact of this substitution on proteolytic cleavage is being assessed. Finally, an amino acid change in exon 3 of the MIP1A gene is associated with resistance to infection in African American cohort participants. This is the most significant association with HIV-1 transmission yet reported in this racial group.
| Modi, William S; O'Brien, Thomas R; Vlahov, David et al. (2003) Haplotype diversity in the interleukin-4 gene is not associated with HIV-1 transmission and AIDS progression. Immunogenetics 55:157-64 |
| Modi, William S; Goedert, James J; Strathdee, Steffanie et al. (2003) MCP-1-MCP-3-Eotaxin gene cluster influences HIV-1 transmission. AIDS 17:2357-65 |
