Recent advances in human genetics have enabled the identification of various mutations responsible for disease. Such advances include collections of families and populations presenting clinical phenotypes, genome sequence and polymorphism databases, mathematical algorithms and computer programs for computational purposes, and novel applications of pedigree and linkage disequilibrum (LD) analyses. LD is the non-random association between alleles at different loci. By tracking genetic markers in LD with a disease phenotype, a genomic region harboring a causal variant can be localized. With association studies, it is necessary to determine the haplotype structure of any given region. Recent studies have demonstrated that many regions of the human genome are characterized by segments or blocks of limited haplotype diversity due to high levels of LD between genetic markers. Chemotactic cytokines are known to direct the migration of specific subsets of leukocytes to sites of infection and inflammation. Further, the natural chemokine receptors CCR5 and CXCR4 are HIV-1 coreceptors. About 40 human chemokine genes are found at eight different chromosomal locations, with major clusters on chromosomes 4 and 17. We are focusing on 16 Chemotactic cytokines (CC) genes located at 17q12-21. Nine of these genes (CCL2, CCL7, CCL11, CCL5, CCL14, CCL3, CCL4, CCL3L1, and CCL4L1) have been implicated in HIV-1/AIDS pathogenesis based upon tissue culture, cellular immunological and virus infection assays. In fact CCL3L1 has the strongest binding affinity of all ligands for CCR5, and is thus an excellent candidate for an HIV-1 entry inhibitor. A comprehensive haplotype analysis is being carried out using 80 single nucleotide polymorphisms (SNPs) covering 400 kb in 200 individuals from each of three racial groups: European Americans, African Americans and Chinese. Approximately 40 'tagged' SNPs will be selected and subsequently genotyped in 4000 subjects enrolled in HIV-1/AIDS cohorts. We have already identified and published genetic influences on HIV-1/AIDS for two gene regions, one containing CCR5 (RANTES) and one containing CCL2-CCL7-CCL11 (MCP-1, MCP-3, and EOTAXIN). In addition, SNP CCL3 459 C/T is associated with an increased rate to AIDS-87 in European Americans (p=0.003), and SNP CCL4 662 C/G is associated with apparent resistance to infection in African Americans (p=0.01). Subjects are also available for lung cancer, skin cancer and Hodgkin's disease studies, and are being developed for hepatitis and nasopharyngeal carcinoma. Once the studies 'tagged' SNPs have been identified they will be genotyped in all disease populations.
| 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 |
