TY - JOUR
T1 - 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
AU - Irvin, Marguerite R.
AU - Sitlani, Colleen M.
AU - Noordam, Raymond
AU - Avery, Christie L.
AU - Bis, Joshua C.
AU - Floyd, James S.
AU - Li, Jin
AU - Limdi, Nita A.
AU - Srinivasasainagendra, Vinodh
AU - Stewart, James
AU - de Mutsert, Renée
AU - Mook-Kanamori, Dennis O.
AU - Lipovich, Leonard
AU - Kleinbrink, Erica L.
AU - Smith, Albert
AU - Bartz, Traci M.
AU - Whitsel, Eric A.
AU - Uitterlinden, Andre G.
AU - Wiggins, Kerri L.
AU - Wilson, James G.
AU - Zhi, Degui
AU - Stricker, Bruno H.
AU - Rotter, Jerome I.
AU - Arnett, Donna K.
AU - Psaty, Bruce M.
AU - Lange, Leslie A.
N1 - Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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 × 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 × 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.
AB - 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 × 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 × 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.
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U2 - 10.1038/s41397-018-0021-9
DO - 10.1038/s41397-018-0021-9
M3 - Article
C2 - 29855607
AN - SCOPUS:85047935937
SN - 1470-269X
VL - 19
SP - 97
EP - 108
JO - Pharmacogenomics Journal
JF - Pharmacogenomics Journal
IS - 1
ER -