The study of human genetic variation holds tremendous promise for elucidating the molecular basis of disease. A number of Mendelian disorders have been tracked using linkage analyses in families, while non-Mendelian traits have been more difficult to assess. The present availability of single nucleotide polymorphism (SNP) databases enable the utilization of linkage disequilibrium (LD) approaches toward addressing complex phenotypes. LD is the association between alleles at different loci. Since a disease mutation arises on a particular genetic background, by identifying genetic markers in LD with a disease phenotype, a genomic region harboring a causal variant can be localized. Recent studies have demonstrated that the human genome is characterized by 25 kb -100 kb segments or blocks of limited haplotype diversity due to high levels of LD. In association studies, the a priori determination of haplotype structure in a given region can reduce genotyping expenses by avoiding redundant markers. Haplotype variability and LD are being measured in two genomic regions containing cytokine genes in order to identify a set of genetic markers useful in association studies of infectious diseases and cancer. One region includes 250 kb around the SDF-1 cytokine gene on chromosome 10. Analyses reveal that LD is extensive and haplotype blocks of 70 kb and 50 kb have been seen in European Americans. In addition, novel associations with SDF-1 -5757 G/A have been identified. This SNP is associated with susceptibility to HIV-1 infection in European Americans (p=0.008), and with an increased rate to AIDS progression in African Americans (p=0.03). The second region under study includes 600 kb containing 16 CC chemokines on chromosome 17. In the area containing MCP1, eotaxin, MCP3, MCP2, MCP4 and I309 haplotype blocks of 20, 76, 25 and 41 kb have been described. About 1.5 Mb downstream the gene cluster containing RANTES, MIP1A, PARC, MIP1B, LEC, and MPIF1 resides. Haplotype blocks of 65, 40, and 55 kb in size have been identified. Collectively, these analyses reveal that about 35 SNPs represent the haplotype variation on these two chromosomes, and will be used for subsequent disease cohort genotyping. In addition to HIV-1/AIDS, cohorts are available for lung cancer, breast cancer and Hodgkin's disease, and are being developed for hepatitis and nasopharyngeal carcinoma.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005384-19
Application #
6761536
Study Section
(LGD)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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