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 J. 2019 Feb;19(1):97-108. doi: 10.1038/s41397-018-0021-9. Epub 2018 Jun 1.

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 × 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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Americans / genetics*
  • Aged
  • Antihypertensive Agents / therapeutic use
  • Chromosomes, Human, Pair 5 / genetics
  • Europe
  • European Continental Ancestry Group / genetics*
  • Female
  • Genome-Wide Association Study / methods
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Peptidyl-Dipeptidase A / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Potassium / blood*
  • Sodium Chloride Symporter Inhibitors / therapeutic use*

Substances

  • Antihypertensive Agents
  • Sodium Chloride Symporter Inhibitors
  • ACE protein, human
  • Peptidyl-Dipeptidase A
  • Potassium

Grant support