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

Abstract

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 (SBP) and/or diastolic BP decreased 12 mmHg (P = 4.5E‐05) to 30 mmHg (P = 6.4E‐04) among AF only. In contrast, after moderate intensity over 19 h among ACE and CYP11B2 variants passing multiple testing thresholds, as the #MA increased, SBP increased 21 mmHg (P = 8.0E‐04) to 22 mmHg (P = 8.2E‐04) among AF only. In this replication study, ACE,AGTR1,CYP11B2, and ADD1 variants exhibited associations with PEH after vigorous, but not moderate intensity exercise among AF only. Renal variants should be explored further with a multi‐level “omics” approach for associations with PEH among a large, ethnically diverse sample of adults with hypertension.

FURINvariant associations with postexercise hypotension are intensity and race dependent

“…The subjects and data from two previous reports (Pescatello et al. , ) were used in the current study as well. We obtained a blood sample for deep‐targeted exon sequencing and a fasting cardiometabolic profile at the orientation session.…”

“…The screening technique has been described in detail previously (Pescatello et al. , ). Briefly, we analyzed genotypic values coded as the number of MA (#MA) for 645 variants from 41 genes (Pescatello et al.…”

“…Briefly, we analyzed genotypic values coded as the number of MA (#MA) for 645 variants from 41 genes (Pescatello et al. , ). Linear r mixed models were fit for each race separately that included polynomial time (order 3), polymorphism under an additive model, and polymorphism x time interactions as covariates, BP response as the dependent variable, and a first‐order autoregressive (AR1) correlation structure for the 19 repeated observations within subject.…”

“…As stated in our previous reports (Pescatello et al. , ), for each polymorphism passing the multiple testing threshold, covariates were chosen for inclusion in the final models if they were marginally associated ( P < 0.05) with the BP response using models fit by maximum likelihood (ML). AR1 provided the best fit in terms of Akaike Information Criteria in all cases compared to other possible within subject correlation structures (e.g., compound symmetry and independent structures).…”

Preliminary study about the relationship between estimated training status and RAS polymorphisms on blood pressure and ACE activity in the elderly

“…In addition, Montrezol et al showed a reduction on BP in homozygous ACE (I/D) genotypes and no changes in I alleles carriers after a resistance training programme, 18 and Pescatello et al observed the angiotensinogen-converting enzyme (ACE), angiotensin type 1 receptor (AGTR1), aldosterone synthase (CYP11B2), and adducin (ADD1) genes exhibited intensity-dependent associations with the ambulatory BP and postexercise hypotension (PEH) response after acute exercise. 19 However, this effect was observed after vigorous, but not moderate intensity exercise among African Americans.…”