Using a candidate gene approach, the LGD has identified nearly 20 HIV/AIDS restriction genes (ARGs) that influence susceptibility to viral infection or the rate of disease progression. However, since the biology of AIDS is incompletely known, a whole genome association analysis may reveal additional significant ARGs. While panels suitable for high-throughput genotyping containing 500,000 or more single nucleotide polymorphisms (SNPs) have been developed, they may not include """"""""operative"""""""" causal SNPs. It is thus necessary to evaluate the efficiency of linkage disequilibrium (LD) with adjacent """"""""proxy"""""""" SNPs (pSNPs) to identify operative SNPs. Additionally, we wished to evaluate the efficiency of haplotypes carrying the operative SNPs (Haps+) or haplotypes inferred from SNPs across the ARG region without the operative SNP to identify operative SNPs (Haps-).A panel of 332 SNPs spaced at an average of 16 kb across 800 kb from seven segments on six chromosomes was genotyped on 2,139 European American subjects from six HIV/AIDS cohorts. The genomic regions surveyed included five segments containing previously reported ARGs as well as two control regions not previously known to contain ARGs. Analysis results were obtained with several bioinformatics tools. The ARG ANALYSIS program performed association analyses for infection or progression. Haplotypes inferred by the EM algorithm using the BLOCKHEAD program were analyzed in biallelic genotype format. ARG ARRAY displays P-values in arrays of color-coded squares where rows correspond to the marker and columns refer to the test. Colors range from light gray for insignificant results to red or black for highly significant P-values. ARG RANK graphically compares the significance and strengths of associations of a marker with those of other markers tested. The ARG TRACKS program provides a six-page report with detailed analysis results. The SNPHWE-Plus program performs chi-square and exact tests for departure from Hardy-Weinberg equilibrium and additionally computes expected and observed heterozygosity, the HWE disequilibrium coefficient, and the coefficient of inbreeding, FIS.For each of 8 ARGs, three tests were performed (pSNP, Haps+, and Haps-) to give a total of 24 ARG tests. Of these 13 (54%) resulted in recognizable positive signals. Of the three types of tests, the percentage of positive results was highest for pSNPs. These results indicate that a genome scan with the same marker density and number of subjects as this pilot experiment could detect the majority of ARGs in the entire genome that have effects with odds ratios comparable to those of the ARGs included in the study.
|Nelson, George W; O'Brien, Stephen J (2006) Using mutual information to measure the impact of multiple genetic factors on AIDS. J Acquir Immune Defic Syndr 42:347-54|
|Modi, William S; Lautenberger, James; An, Ping et al. (2006) Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. Am J Hum Genet 79:120-8|
|An, Ping; Vlahov, David; Margolick, Joseph B et al. (2003) A tumor necrosis factor-alpha-inducible promoter variant of interferon-gamma accelerates CD4+ T cell depletion in human immunodeficiency virus-1-infected individuals. J Infect Dis 188:228-31|