Mark H Kuniholm1, Hua Liang, Kathryn Anastos, Deborah Gustafson, Seble Kassaye, Marek Nowicki, Beverly E Sha, Emilia J Pawlowski, Stephen J Gange, Bradley E Aouizerat, Tatiana Pushkarsky, Michael I Bukrinsky, Vinayaka R Prasad. 1. aDepartment of Epidemiology and Biostatistics, University at Albany, State University of New York, Rensselaer, New York bDepartment of Statistics. George Washington University, Washington, DC cDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx dDepartment of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx eDepartment of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York fDepartment of Medicine, Georgetown University Medical Center, Washington, DC gDepartment of Medicine, University of Southern California, Los Angeles, California hDepartment of Medicine, Rush University Medical Center, Chicago, Illinois iDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland jBluestone Center for Clinical Research kDepartment of Oral and Maxillofacial Surgery, New York University, New York, New York lDepartment of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC mDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
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.
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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