Genome-Wide Association Study Implicates PARD3B-Based AIDS Restriction
Journal of Infectious Diseases
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.
Troyer, Jennifer L.; George W. Nelson; J. A. Lautenberger; Leslie Chinn; Carl McIntosh; Randall C. Johnson; Efe Sezgin; Bailey Kessing; Michael Malasky; Sher L. Hendrickson; Guan Li; J. U. Pontius; M. Tang; Ping An; Cheryl Winkler; Sophie Limou; Sigrid le Clerc; Olivier Delaneau; Jean-Francois Zagury; Hanneke Schuitemaker; Danielle van Manen; Jay H. Bream; Edward Gomperts; Susan Buchbinder; James J. Goedert; Gregory Kirk; and Stephen J. O'Brien. 2011. "Genome-Wide Association Study Implicates PARD3B-Based AIDS Restriction." Journal of Infectious Diseases 203, (10): 1491-1502. http://nsuworks.nova.edu/cnso_bio_facarticles/446