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 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; 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, B, 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 ; 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.
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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.",
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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

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

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