PCSK9 variation and association with blood pressure in African Americans

Preliminary findings from the HyperGEN and REGARDS studies

Ngan T. Tran, Stella Aslibekyan, Hemant K. Tiwari, Degui Zhi, Yun Ju Sung, Steven Hunt, D. C. Rao, Ulrich Broeckel, Suzanne E. Judd, Paul Muntner, Shia T. Kent, Donna K. Arnett, Marguerite R. Irvin

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, P = 0.05 and rs9730100: β = 1.0, P = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (P = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies.

Original languageEnglish
Article number136
JournalFrontiers in Genetics
Volume6
Issue numberAPR
DOIs
Publication statusPublished - 2015
Externally publishedYes

Fingerprint

Molecular Epidemiology
African Americans
Stroke
Blood Pressure
Hypertension
Single Nucleotide Polymorphism
LDL Receptors
Validation Studies
Genome-Wide Association Study
Hyperlipidemias
Linear Models
Cardiovascular Diseases
Smoking

Keywords

  • Blood pressure
  • Dyslipidemia
  • Hypertension
  • Low-density lipoprotein cholesterol
  • PCSK9

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Genetics(clinical)

Cite this

PCSK9 variation and association with blood pressure in African Americans : Preliminary findings from the HyperGEN and REGARDS studies. / Tran, Ngan T.; Aslibekyan, Stella; Tiwari, Hemant K.; Zhi, Degui; Sung, Yun Ju; Hunt, Steven; Rao, D. C.; Broeckel, Ulrich; Judd, Suzanne E.; Muntner, Paul; Kent, Shia T.; Arnett, Donna K.; Irvin, Marguerite R.

In: Frontiers in Genetics, Vol. 6, No. APR, 136, 2015.

Research output: Contribution to journalArticle

Tran, NT, Aslibekyan, S, Tiwari, HK, Zhi, D, Sung, YJ, Hunt, S, Rao, DC, Broeckel, U, Judd, SE, Muntner, P, Kent, ST, Arnett, DK & Irvin, MR 2015, 'PCSK9 variation and association with blood pressure in African Americans: Preliminary findings from the HyperGEN and REGARDS studies', Frontiers in Genetics, vol. 6, no. APR, 136. https://doi.org/10.3389/fgene.2015.00136
Tran, Ngan T. ; Aslibekyan, Stella ; Tiwari, Hemant K. ; Zhi, Degui ; Sung, Yun Ju ; Hunt, Steven ; Rao, D. C. ; Broeckel, Ulrich ; Judd, Suzanne E. ; Muntner, Paul ; Kent, Shia T. ; Arnett, Donna K. ; Irvin, Marguerite R. / PCSK9 variation and association with blood pressure in African Americans : Preliminary findings from the HyperGEN and REGARDS studies. In: Frontiers in Genetics. 2015 ; Vol. 6, No. APR.
@article{76e06a80429949f8a1032df0e7980ef4,
title = "PCSK9 variation and association with blood pressure in African Americans: Preliminary findings from the HyperGEN and REGARDS studies",
abstract = "Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, P = 0.05 and rs9730100: β = 1.0, P = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (P = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies.",
keywords = "Blood pressure, Dyslipidemia, Hypertension, Low-density lipoprotein cholesterol, PCSK9",
author = "Tran, {Ngan T.} and Stella Aslibekyan and Tiwari, {Hemant K.} and Degui Zhi and Sung, {Yun Ju} and Steven Hunt and Rao, {D. C.} and Ulrich Broeckel and Judd, {Suzanne E.} and Paul Muntner and Kent, {Shia T.} and Arnett, {Donna K.} and Irvin, {Marguerite R.}",
year = "2015",
doi = "10.3389/fgene.2015.00136",
language = "English",
volume = "6",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media S. A.",
number = "APR",

}

TY - JOUR

T1 - PCSK9 variation and association with blood pressure in African Americans

T2 - Preliminary findings from the HyperGEN and REGARDS studies

AU - Tran, Ngan T.

AU - Aslibekyan, Stella

AU - Tiwari, Hemant K.

AU - Zhi, Degui

AU - Sung, Yun Ju

AU - Hunt, Steven

AU - Rao, D. C.

AU - Broeckel, Ulrich

AU - Judd, Suzanne E.

AU - Muntner, Paul

AU - Kent, Shia T.

AU - Arnett, Donna K.

AU - Irvin, Marguerite R.

PY - 2015

Y1 - 2015

N2 - Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, P = 0.05 and rs9730100: β = 1.0, P = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (P = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies.

AB - Proprotein convertase subtilisin/kexin type 9 (encoded by PCSK9) plays a well-known role in the regulation of low-density lipoprotein (LDL) receptors, and an inhibitor of this enzyme is a promising new therapeutic for hyperlipidemia. Recently, animal and human studies also implicate PCSK9 genetic variation in the regulation of blood pressure. The goal of this study was to examine if common and rare polymorphisms in PCSK9 are associated with blood pressure in an African-American population at high risk for cardiovascular disease. Using genomic data assayed on the Affymetrix 6.0 array (n = 1199) and the Illumina HumanExome Beadchip (n = 1966) from the Hypertension Genetic Epidemiology Network (HyperGEN), we tested the association of PCSK9 polymorphisms with blood pressure. We used linear mixed models and the sequence kernel association test (SKAT) to assess the association of 31 common and 19 rare variants with blood pressure. The models were adjusted for age, sex, center, smoking status, principal components for ancestry and diabetes as fixed effects and family as a random effect. The results showed a marginally significant effect of two genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) (rs12048828: β = 1.8, P = 0.05 and rs9730100: β = 1.0, P = 0.05) with diastolic blood pressure (DBP); however these results were not significant after correction for multiple testing. Rare variants were cumulatively associated with DBP (P = 0.04), an effect that was strengthened by restriction to non-synonymous or stop-gain SNPs (P = 0.02). While gene-based results for DBP did not replicate (P = 0.36), we found an association with SBP (P = 0.04) in the Reasons for Geographic And Racial Differences in Stroke study (REGARDS). The findings here suggest rare variants in PCSK9 may influence blood pressure among African Americans, laying the ground work for further validation studies.

KW - Blood pressure

KW - Dyslipidemia

KW - Hypertension

KW - Low-density lipoprotein cholesterol

KW - PCSK9

UR - http://www.scopus.com/inward/record.url?scp=84940046533&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940046533&partnerID=8YFLogxK

U2 - 10.3389/fgene.2015.00136

DO - 10.3389/fgene.2015.00136

M3 - Article

VL - 6

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

IS - APR

M1 - 136

ER -