Genome-wide meta-analysis of SNP and antihypertensive medication interactions on left ventricular traits in African Americans

Mol Genet Genomic Med. 2019 Oct;7(10):e00788. doi: 10.1002/mgg3.788. Epub 2019 Aug 13.

Abstract

Background: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography.

Methods: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates.

Results: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10-8 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population.

Conclusions: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.

Keywords: GWAS; antihypertensive treatment; left ventricular trait; pharmacogenetics.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Antihypertensive Agents / therapeutic use*
  • Black or African American / genetics
  • Black or African American / statistics & numerical data
  • Calcium Channel Blockers / therapeutic use
  • Humans
  • Observational Studies as Topic
  • Pharmacogenomic Variants*
  • Polymorphism, Single Nucleotide*
  • Sodium Chloride Symporter Inhibitors / therapeutic use
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / epidemiology
  • Ventricular Dysfunction, Left / genetics*

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Calcium Channel Blockers
  • Sodium Chloride Symporter Inhibitors

Grants and funding