OBJECTIVE
To assess variation in genes that regulate cholesterol metabolism in relation to the natural history of HIV infection.
DESIGN
Cross-sectional and longitudinal analysis of the Women's Interagency HIV Study (WIHS).
METHODS
We examined 2,050 single nucleotide polymorphisms (SNPs) in 19 genes known to regulate cholesterol metabolism in relation to HIV viral load and CD4 T cell levels in a multiracial cohort of 1,066 antiretroviral therapy (ART) naïve women.
RESULTS
Six SNPs were associated with both HIV viral load and CD4 T cell levels at a false discovery rate (FDR) of 0.01. Bioinformatics tools did not predict functional activity for five SNPs, located in introns of NCOR2, RXRA and TTC39B. Rs17111557 located in the 3' untranslated region (UTR) of PCSK9 putatively affects binding of hsa-miR-548t-5p and hsa-miR-4796-3p, which could regulate PCSK9 expression levels. Interrogation of rs17111557 revealed stronger associations in the subset of women with HIV/hepatitis C virus (HCV) co-infection (n = 408, 38% of women). Rs17111557 was also associated with low-density lipoprotein cholesterol (LDL-C) levels in HIV/HCV co-infected (β: -10.4; 95% CI: -17.9, -2.9; P = 0.007), but not in HIV monoinfected (β:1.2; 95% CI: -6.3, 8.6; P = 0.76) women in adjusted analysis.
CONCLUSIONS
PCSK9 polymorphism may affect HIV pathogenesis, particularly in HIV/HCV co-infected women. A likely mechanism for this effect is PCSK9-mediated regulation of cholesterol metabolism. Replication in independent cohorts is needed to clarify the generalizability of the observed associations.