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

Mark H. Kuniholm; 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

doi:10.1097/QAD.0000000000001648

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

Mark H. Kuniholm, 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

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2483-2492
Number of pages	10
Journal	AIDS
Volume	31
Issue number	18
DOIs	https://doi.org/10.1097/QAD.0000000000001648
State	Published - Nov 28 2017

Keywords

African American
HIV
cholesterol
hepatitis C virus
proprotein convertase subtilisin/kexin type 9

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1097/QAD.0000000000001648

Cite this

Kuniholm, M. H., Liang, H., Anastos, K., Gustafson, D., Kassaye, S., Nowicki, M., Sha, B. E., Pawlowski, E. J., Gange, S. J., Aouizerat, B. E., Pushkarsky, T., Bukrinsky, M. I., & Prasad, V. R. (2017). 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. AIDS, 31(18), 2483-2492. https://doi.org/10.1097/QAD.0000000000001648

Kuniholm, MH, Liang, H, Anastos, K, Gustafson, D, Kassaye, S, Nowicki, M, Sha, BE, Pawlowski, EJ, Gange, SJ, Aouizerat, BE, Pushkarsky, T, Bukrinsky, MI & Prasad, VR 2017, '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', AIDS, vol. 31, no. 18, pp. 2483-2492. https://doi.org/10.1097/QAD.0000000000001648

@article{b86dfd6e9b0b4a1cb8d2b63057ffcc27,

title = "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",

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.",

keywords = "African American, HIV, cholesterol, hepatitis C virus, proprotein convertase subtilisin/kexin type 9",

author = "Kuniholm, {Mark H.} and Hua Liang and Kathryn Anastos and Deborah Gustafson and Seble Kassaye and Marek Nowicki and Sha, {Beverly E.} and Pawlowski, {Emilia J.} and Gange, {Stephen J.} and Aouizerat, {Bradley E.} and Tatiana Pushkarsky and Bukrinsky, {Michael I.} and Prasad, {Vinayaka R.}",

note = "Funding Information: The project was supported in part by R37AI030861 and T32AI007501 (to V.R.P.) and P30AI117970 (to. H.L. and M.I.B), R01HL131473 and R01HL101274 (to M.I.B). Additional data in this manuscript were collected by the Women{\textquoteright}s Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health. WIHS (Principal Investigators): Bronx WIHS (K.A.), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and D. G.), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (S.K.), U01-AI-034994; Connie Wofsy Women{\textquoteright}s HIV Study, Northern California (Ruth Greenblatt, B.E.A., and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (S.J.G. and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I–WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Mental Health. Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Deafness and other Communication Disorders, and the National Institutes of Health Office of Research on Women{\textquoteright}s Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA). Publisher Copyright: Copyright {\textcopyright} 2017 Wolters Kluwer Health, Inc. All rights reserved.",

year = "2017",

month = nov,

day = "28",

doi = "10.1097/QAD.0000000000001648",

language = "English (US)",

volume = "31",

pages = "2483--2492",

journal = "AIDS",

issn = "0269-9370",

publisher = "Lippincott Williams and Wilkins",

number = "18",

}

TY - JOUR

T1 - 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

AU - Kuniholm, Mark H.

AU - Liang, Hua

AU - Anastos, Kathryn

AU - Gustafson, Deborah

AU - Kassaye, Seble

AU - Nowicki, Marek

AU - Sha, Beverly E.

AU - Pawlowski, Emilia J.

AU - Gange, Stephen J.

AU - Aouizerat, Bradley E.

AU - Pushkarsky, Tatiana

AU - Bukrinsky, Michael I.

AU - Prasad, Vinayaka R.

N1 - Funding Information: The project was supported in part by R37AI030861 and T32AI007501 (to V.R.P.) and P30AI117970 (to. H.L. and M.I.B), R01HL131473 and R01HL101274 (to M.I.B). Additional data in this manuscript were collected by the Women’s Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health. WIHS (Principal Investigators): Bronx WIHS (K.A.), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and D. G.), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (S.K.), U01-AI-034994; Connie Wofsy Women’s HIV Study, Northern California (Ruth Greenblatt, B.E.A., and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (S.J.G. and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I–WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Mental Health. Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Deafness and other Communication Disorders, and the National Institutes of Health Office of Research on Women’s Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA). Publisher Copyright: Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

PY - 2017/11/28

Y1 - 2017/11/28

N2 - 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.

AB - 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.

KW - African American

KW - HIV

KW - cholesterol

KW - hepatitis C virus

KW - proprotein convertase subtilisin/kexin type 9

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DO - 10.1097/QAD.0000000000001648

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EP - 2492

JO - AIDS

JF - AIDS

IS - 18

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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