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.

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

Journal: The pharmacogenomics journal 2019;19(1):97-108

PMID: 29855607

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) 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; 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.

Address: Department of Epidemiology, University of Alabama, Birmingham, AL, USA. [email protected].; Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.; Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, USA.; Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.; Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.; Department of Neurology, University of Alabama, Birmingham, AL, USA.; Department of Biostatistics, University of Alabama, Birmingham, AL, USA.; Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, USA.; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Clinical Epidemiology and Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.; Department of Neurology, Wayne State University, Detroit, MI, USA.; Center Molecular Medicine/Genetics, Wayne State University School of Medicine, Detroit, MI, USA.; Icelandic Heart Association, Kopavogur, Iceland, University of Iceland, Reykjavik, Iceland.; Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, USA.; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.; Department of Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.; School of Biomedical Informatics, University of Texas Health Sciences Center at Houston, Houston, TX, USA.; Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.; Inspectorate of Health Care, Utrecht, The Netherlands.; Institute for Translational Genomics and Population Sciences and Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.; College of Public Health, University of Kentucky, Lexington, KY, USA.; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, Health Services, University of Washington, Seattle, WA, USA.; Group Health Research Institute, Group Health Cooperatives, Seattle, WA, USA.; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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