Genome-Wide Meta-Analysis of SNP-by9-ACEI/ARB and SNP-by-Thiazide Diuretic and Effect on Serum Potassium in Cohorts of European and African Ancestry

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Irvin, Marguerite Ryan; Sitlani, Colleen M.; Noordam, Raymond; Avery, Christy L.; Bis, Joshua C.; Floyd, James S.; Li, Jin; Limdi, Nita A.; Srinivasasainagendra, Vinodh; & Stewart, James D., et al. (2019). Genome-Wide Meta-Analysis of SNP-by9-ACEI/ARB and SNP-by-Thiazide Diuretic and Effect on Serum Potassium in Cohorts of European and African Ancestry. Pharmacogenomics Journal, 19(1), 97-108. PMCID: PMC6274589

Abstract

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 x 10(-8)) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 x 10(-8); ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

URL

http://dx.doi.org/10.1038/s41397-018-0021-9

Reference Type

Journal Article

Year Published

2019

Journal Title

Pharmacogenomics Journal

Author(s)

Irvin, Marguerite Ryan
Sitlani, Colleen M.
Noordam, Raymond
Avery, Christy L.
Bis, Joshua C.
Floyd, James S.
Li, Jin
Limdi, Nita A.
Srinivasasainagendra, Vinodh
Stewart, James D.
de Mutsert, Renee
Mook-Kanamori, Dennis O.
Lipovich, Leonard
Kleinbrink, Erica L.
Smith, Albert V.
Bartz, Traci M.
Whitsel, Eric A.
Uitterlinden, Andre G.
Wiggins, Kerri L.
Wilson, James G.
Zhi, Degui
Stricker, Bruno H.
Rotter, Jerome I.
Arnett, Donna K.
Psaty, Bruce M.
Lange, Leslie A.

PMCID

PMC6274589

ORCiD

Avery - 0000-0002-1044-8162