Showing papers by "George W. Nelson published in 2000"

Polygenic and multifactorial disease gene association in man: Lessons from AIDS

Abstract: ▪ Abstract In an age when the majority of monogenic human disease genes have been identified, a particular challenge for the coming generation of human geneticists will be resolving complex polygenic and multifactorial diseases. The tools of molecular and population genetic association have much potential as well as peril in uncovering small cryptic genetic effects in disease. We have used a candidate gene approach to identify eight distinct human loci with alleles that in different ways influence the outcome of exposure to HIV-1, the AIDS virus. The successes in these gene hunts have validated the approach and illustrate the strengths and limitations of association analysis in an actual case history. The integration of genetic associations, well-described clinical cohorts, extensive basic research on AIDS pathogenesis, and functional interpretation of gene connections to disease offers a formula for detecting such genes in complex human genetic phenotypes.

Influence of CCR5 promoter haplotypes on AIDS progression in African-Americans.

Abstract: Objectives: To test the hypothesis that the CCR5 promoter variants in HIV-1-infected African-Americans affect the rate of progression to AIDS and to determine the extent of linkage disequilibrium between the CCR5P1 allele and the CCR5 59029A variant (referred to here as CCR5-2459A), both of which have been shown independently to accelerate AIDS progression in Caucasians. Design: We used survival analysis to assess the effects of CCR5 promoter variants in HIV-1 seroincident Caucasians and African-Americans. Subjects and methods: Genotypes were determined for 806 Caucasians and 1067 African-Americans, which included 700 seroconverters, enrolled in four HIV/AIDS natural history cohort studies. These genotypes were used to determine linkage and haplotypes for CCR2 and CCR5 alleles. Survival analysis was used to assess the effect of CCR2, CCR5, and CCR5 promoter haplotypes on progression to AIDS in seroincident African-Americans. Results: A survey of Caucasians and African-Americans demonstrated complete linkage disequilibrium between CCR5P1 and CCR5-2459A sites. The composite CCR5P1 haplotype (including the CCR5-2459A allele) is shown to be associated with rapid progression to AIDS endpoints in both African-American and Caucasian cohorts, but the effect is recessive in Caucasians and dominant in African-Americans. This is probably due to the presence of modulating genes or as yet unidentified polymorphisms that may differ between racial groups.

The Human Genes that Limit AIDS

Abstract: The development of AIDS symptoms is a gradual process whereby a diverse population of HIV-1 genomes replicate in macrophages, monocytes, and T cells, challenging the immune system to its extreme. The cellular compartments and machinery that facilitate the process are human gene products that are punctuated by allelic variation that in some cases, determines the efficiency and kinetics of disease progression. Using molecular genetic typing of epidemiologic cohorts of HIV-1-infected study participants, we have searched for host genetic variants in genes whose products participate in HIV-1 replication. To date we have discovered attributable genetic influence on HIV-1 infection, disease progression, and AIDS sequelae involving coding and promoter regions of several human genes, namely CCR5, CCR2, SDF1, HLA-A, -B, and -C. This report will highlight the discovery, characterization and functioning of the multi-genic influences on the outcomes of HIV-1 infection and the influence of these variants on epidemiologic heterogeneity of the AIDS epidemic.