Deep‐targeted exon sequencing reveals renal polymorphisms associate with postexercise hypotension among African Americans

摘要

We found variants from the Angiotensinogen‐Converting Enzyme (ACE), Angiotensin Type 1 Receptor (AGTR1), Aldosterone Synthase (CYP11B2), and Adducin (ADD1) genes exhibited intensity‐dependent associations with the ambulatory blood pressure (BP) response following acute exercise, or postexercise hypotension (PEH). In a validation cohort, we sequenced exons from these genes for their associations with PEH. Obese (30.9 ± 3.6 kg m⁻²) adults (n = 23; 61% African Americans [AF], 39% Caucasian) 42.0 ± 9.8 years with hypertension (139.8 ± 10.4/84.6 ± 6.2 mmHg) completed three random experiments: bouts of vigorous and moderate intensity cycling and control. Subjects wore an ambulatory BP monitor for 19 h. We performed deep‐targeted exon sequencing using the Illumina TruSeq Custom Amplicon kit. Variant genotypes were coded as number of minor alleles (#MA) and selected for further statistical analysis based upon Bonferonni or Benjamini–Yekutieli multiple testing corrected p‐values under time adjusted linear models for 19 hourly BP measurements per subject. After vigorous intensity over 19 h among ACE,AGTR1,CYP11B2, and ADD1 variants passing multiple testing thresholds, as the #MA increased, systolic ( style="fixed-case">SBP) and/or diastolic style="fixed-case">BP decreased 12 mmHg (P = 4.5E‐05) to 30 mmHg (P = 6.4E‐04) among style="fixed-case">AF only. In contrast, after moderate intensity over 19 h among style="fixed-case">ACE and style="fixed-case">CYP11B2 variants passing multiple testing thresholds, as the # style="fixed-case">MA increased, style="fixed-case">SBP increased 21 mmHg (P = 8.0E‐04) to 22 mmHg (P = 8.2E‐04) among style="fixed-case">AF only. In this replication study, style="fixed-case">ACE, style="fixed-case">AGTR1, style="fixed-case">CYP11B2, and style="fixed-case">ADD1 variants exhibited associations with style="fixed-case">PEH after vigorous, but not moderate intensity exercise among style="fixed-case">AF only. Renal variants should be explored further with a multi‐level “omics” approach for associations with style="fixed-case">PEH among a large, ethnically diverse sample of adults with hypertension.