Association of a 3′ untranslated region polymorphism in proprotein convertase subtilisin/kexin type 9 with HIV viral load and CD4+ levels in HIV/hepatitis C virus coinfected women

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Abstract

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.

Methods:

We examined 2050 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 1066 antiretroviral therapy-naive women.

Results:

Six SNPs were associated with both HIV viral load and CD4+ T-cell levels at a false discovery rate of 0.01. Bioinformatics tools did not predict functional activity for five SNPs, located in introns of nuclear receptor corepressor 2, retinoid X receptor alpha (RXRA), and tetratricopeptide repeat domain 39B. Rs17111557 located in the 3′ untranslated region of proprotein convertase subtilisin/kexin type 9 (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) coinfection (n = 408, 38% of women). Rs17111557 was also associated with low-density lipoprotein cholesterol levels in HIV/HCV coinfected (β: −10.4; 95% confidence interval: −17.9, −2.9; P = 0.007), but not in HIV monoinfected (β:1.2; 95% confidence interval: −6.3, 8.6; P = 0.76) women in adjusted analysis.

Conclusion:

PCSK9 polymorphism may affect HIV pathogenesis, particularly in HIV/HCV coinfected 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.

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