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||Genome-wide association study implicates PARD3B-based AIDS restriction.
||Troyer JL, Nelson GW, Lautenberger JA, Chinn L, McIntosh C, Johnson RC, Sezgin E, Kessing B, Malasky M, Hendrickson SL, Li G, Pontius J, Tang M, An P, Winkler CA, Limou S, Le Clerc S, Delaneau O, Zagury JF, Schuitemaker H, van Manen D, Bream JH, Gomperts ED, Buchbinder S, Goedert JJ, Kirk GD, O'Brien SJ
||J Infect Dis
||2011 May 15
||BACKGROUND: Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression. METHODS: European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model). RESULTS: Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10(-9)) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10(-8)). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025). CONCLUSIONS: These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression.