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 journalArticle

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 languageEnglish (US)
Pages (from-to)2483-2492
Number of pages10
JournalAIDS
Volume31
Issue number18
DOIs
StatePublished - Nov 28 2017

Fingerprint

3' Untranslated Regions
Viral Load
Hepacivirus
HIV
Single Nucleotide Polymorphism
Cholesterol
Retinoid X Receptor alpha
Confidence Intervals
T-Lymphocytes
Co-Repressor Proteins
Proprotein Convertase 9
Computational Biology
Coinfection
LDL Cholesterol
Introns
Genes
HIV Infections
Cross-Sectional Studies

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

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

In: AIDS, Vol. 31, No. 18, 28.11.2017, p. 2483-2492.

Research output: Contribution to journalArticle

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
Kuniholm, Mark H. ; Liang, Hua ; Anastos, Kathryn ; Gustafson, Deborah ; Kassaye, Seble ; Nowicki, Marek ; Sha, Beverly E. ; Pawlowski, Emilia J. ; Gange, Stephen J ; Aouizerat, Bradley E. ; Pushkarsky, Tatiana ; Bukrinsky, Michael I. ; Prasad, Vinayaka R. / 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. In: AIDS. 2017 ; Vol. 31, No. 18. pp. 2483-2492.
@article{2f406e39ca574ad3bc6624faf0ae8775,
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, cholesterol, hepatitis C virus, HIV, 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.}",
year = "2017",
month = "11",
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.

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 - cholesterol

KW - hepatitis C virus

KW - HIV

KW - proprotein convertase subtilisin/kexin type 9

UR - http://www.scopus.com/inward/record.url?scp=85033792628&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85033792628&partnerID=8YFLogxK

U2 - 10.1097/QAD.0000000000001648

DO - 10.1097/QAD.0000000000001648

M3 - Article

VL - 31

SP - 2483

EP - 2492

JO - AIDS

JF - AIDS

SN - 0269-9370

IS - 18

ER -