Genome-wide association analysis of plasma B-type natriuretic peptide in blacks: The Jackson Heart Study

Solomon K. Musani, Ervin R. Fox, Aldi Kraja, Aurelian Bidulescu, Wolfgang Lieb, Honghuang Lin, Ashley Beecham, Ming Huei Chen, Janine F. Felix, Caroline S. Fox, W. H Linda Kao, Sharon L R Kardia, Ching Ti Liu, Mike A. Nalls, Tatjana Rundek, Ralph L Sacco, Jennifer Smith, Yan V. Sun, Gregory Wilson, Zhaogong ZhangThomas H. Mosley, Herman A. Taylor, Ramachandran S. Vasan

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background - Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective; however, in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass. Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms. Methods and Results - We performed a meta-analysis of 2 genome-wide association results from a total of 2790 blacks. We assumed an additive genetic model in an association analysis of imputed 2.5 million single-nucleotide polymorphism dosages with residuals generated from multivariable-adjusted logarithmically transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, P=1.18×10-09) and a novel missense variant in the KLKB1 locus (rs3733402, P=1.75×10-11) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, and an average of 8.1 pg/mL increase was associated with 2 allele copies. In a companion study, single-nucleotide polymorphisms in this loci were cross-checked with genome-wide association results for the aldosterone/renin ratio in individuals of European ancestry, and rs3733402 was genome-wide significant (P<5.0×10-8), suggesting possible shared genetic architecture for these 2 pathways. Other statistically significant relations for these single-nucleotide polymorphisms included the following: rs198389 with systolic blood pressure in blacks (COGENT consortium) and rs198389 and rs3733402 with left ventricular mass in whites (EchoGEN consortium). Conclusions - These findings improve our knowledge of the genetic basis of BNP variation in blacks, demonstrate a possible shared allelic architecture for BNP with aldosterone-renin ratio, and motivate further studies of underlying mechanisms.

Original languageEnglish (US)
Pages (from-to)122-130
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number1
DOIs
StatePublished - Feb 4 2015

Fingerprint

Brain Natriuretic Peptide
Genome-Wide Association Study
Genome
Single Nucleotide Polymorphism
Aldosterone
Renin
Alleles
Blood Pressure
Genetic Models
Genetic Association Studies
Meta-Analysis
Cardiovascular Diseases
Population
Genes

Keywords

  • Genetic association studies
  • Genetics
  • Genome-wide association study
  • Genotype

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

Cite this

Genome-wide association analysis of plasma B-type natriuretic peptide in blacks : The Jackson Heart Study. / Musani, Solomon K.; Fox, Ervin R.; Kraja, Aldi; Bidulescu, Aurelian; Lieb, Wolfgang; Lin, Honghuang; Beecham, Ashley; Chen, Ming Huei; Felix, Janine F.; Fox, Caroline S.; Kao, W. H Linda; Kardia, Sharon L R; Liu, Ching Ti; Nalls, Mike A.; Rundek, Tatjana; Sacco, Ralph L; Smith, Jennifer; Sun, Yan V.; Wilson, Gregory; Zhang, Zhaogong; Mosley, Thomas H.; Taylor, Herman A.; Vasan, Ramachandran S.

In: Circulation: Cardiovascular Genetics, Vol. 8, No. 1, 04.02.2015, p. 122-130.

Research output: Contribution to journalArticle

Musani, SK, Fox, ER, Kraja, A, Bidulescu, A, Lieb, W, Lin, H, Beecham, A, Chen, MH, Felix, JF, Fox, CS, Kao, WHL, Kardia, SLR, Liu, CT, Nalls, MA, Rundek, T, Sacco, RL, Smith, J, Sun, YV, Wilson, G, Zhang, Z, Mosley, TH, Taylor, HA & Vasan, RS 2015, 'Genome-wide association analysis of plasma B-type natriuretic peptide in blacks: The Jackson Heart Study', Circulation: Cardiovascular Genetics, vol. 8, no. 1, pp. 122-130. https://doi.org/10.1161/CIRCGENETICS.114.000900
Musani, Solomon K. ; Fox, Ervin R. ; Kraja, Aldi ; Bidulescu, Aurelian ; Lieb, Wolfgang ; Lin, Honghuang ; Beecham, Ashley ; Chen, Ming Huei ; Felix, Janine F. ; Fox, Caroline S. ; Kao, W. H Linda ; Kardia, Sharon L R ; Liu, Ching Ti ; Nalls, Mike A. ; Rundek, Tatjana ; Sacco, Ralph L ; Smith, Jennifer ; Sun, Yan V. ; Wilson, Gregory ; Zhang, Zhaogong ; Mosley, Thomas H. ; Taylor, Herman A. ; Vasan, Ramachandran S. / Genome-wide association analysis of plasma B-type natriuretic peptide in blacks : The Jackson Heart Study. In: Circulation: Cardiovascular Genetics. 2015 ; Vol. 8, No. 1. pp. 122-130.
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T1 - Genome-wide association analysis of plasma B-type natriuretic peptide in blacks

T2 - The Jackson Heart Study

AU - Musani, Solomon K.

AU - Fox, Ervin R.

AU - Kraja, Aldi

AU - Bidulescu, Aurelian

AU - Lieb, Wolfgang

AU - Lin, Honghuang

AU - Beecham, Ashley

AU - Chen, Ming Huei

AU - Felix, Janine F.

AU - Fox, Caroline S.

AU - Kao, W. H Linda

AU - Kardia, Sharon L R

AU - Liu, Ching Ti

AU - Nalls, Mike A.

AU - Rundek, Tatjana

AU - Sacco, Ralph L

AU - Smith, Jennifer

AU - Sun, Yan V.

AU - Wilson, Gregory

AU - Zhang, Zhaogong

AU - Mosley, Thomas H.

AU - Taylor, Herman A.

AU - Vasan, Ramachandran S.

PY - 2015/2/4

Y1 - 2015/2/4

N2 - Background - Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective; however, in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass. Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms. Methods and Results - We performed a meta-analysis of 2 genome-wide association results from a total of 2790 blacks. We assumed an additive genetic model in an association analysis of imputed 2.5 million single-nucleotide polymorphism dosages with residuals generated from multivariable-adjusted logarithmically transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, P=1.18×10-09) and a novel missense variant in the KLKB1 locus (rs3733402, P=1.75×10-11) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, and an average of 8.1 pg/mL increase was associated with 2 allele copies. In a companion study, single-nucleotide polymorphisms in this loci were cross-checked with genome-wide association results for the aldosterone/renin ratio in individuals of European ancestry, and rs3733402 was genome-wide significant (P<5.0×10-8), suggesting possible shared genetic architecture for these 2 pathways. Other statistically significant relations for these single-nucleotide polymorphisms included the following: rs198389 with systolic blood pressure in blacks (COGENT consortium) and rs198389 and rs3733402 with left ventricular mass in whites (EchoGEN consortium). Conclusions - These findings improve our knowledge of the genetic basis of BNP variation in blacks, demonstrate a possible shared allelic architecture for BNP with aldosterone-renin ratio, and motivate further studies of underlying mechanisms.

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