Deep‐targeted sequencing of endothelial nitric oxide synthase gene exons uncovers exercise intensity and ethnicity‐dependent associations with post‐exercise hypotension

Abstract

In previous studies, we found an endothelial nitric oxide synthase gene (NOS3) variant rs2070744 associated with the ambulatory blood pressure (BP) response following bouts of moderate and vigorous intensity acute exercise, termed post‐exercise hypotension (PEH). In a validation cohort, we sequenced NOS3 exons for associations with PEH. Obese (30.9 ± 3.6 kg.m−2) African American (n = 14) [AF] and Caucasian (n = 9) adults 42.0 ± 9.8 years with hypertension (139.8 ± 10.4/84.6 ± 6.2 mmHg) performed three random experiments: bouts of vigorous and moderate intensity cycling and control. Subjects were attached to an ambulatory BP monitor for 19 h. We performed deep‐targeted exon sequencing with the Illumina TruSeq Custom Amplicon kit. Variant genotypes were coded as number of minor alleles (#MA) and selected for additional statistical analysis based upon Bonferonni or Benjamini–Yekutieli multiple testing‐corrected P‐values under time‐adjusted linear models for 19 hourly BP measurements for each subject. After vigorous intensity over 19 h, among NOS3 variants passing multiple testing thresholds, as the #MA increased in rs891512 (P = 6.4E‐04), rs867225 (P = 6.5E‐04), rs743507 (P = 2.6E‐06), and rs41483644 (P = 2.4E‐04), systolic (SBP) decreased from 17.5 to 33.7 mmHg; and in rs891512 (P = 9.7E‐05), rs867225 (P = 2.6E‐05), rs41483644 (P = 1.6E‐03), rs3730009 (P = 2.6E‐04), and rs77325852 (P = 5.6E‐04), diastolic BP decreased from 11.1 mmHg to 20.3 mmHg among AF only. In contrast, after moderate intensity over 19 h in NOS3 rs3918164, as the #MA increased, SBP increased by 16.6 mmHg (P = 2.4E‐04) among AF only. NOS3 variants exhibited associations with PEH after vigorous, but not moderate intensity exercise among AF only. NOS3 should be studied further for its effects on PEH in a large, ethnically diverse sample of adults with hypertension to confirm our findings.

Predictive Biological Markers in Post-therapeutic Evolution in Obese Patients

“…Duration of exercise had a significant impact on the total cholesterol levels and improves the cardiovascular risk factors [12, 13,16]. Exercise alone is usually not enough to induce significant weight loss.…”

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 subjects then left the laboratory wearing an ambulatory BP monitor until the next morning to familiarize them with the technology (Pescatello et al. ; Ash et al. ,b).…”

“…; Pescatello et al. ) subjects were attached to an ambulatory BP monitor (Oscar2 automatic noninvasive ambulatory BP monitor, Suntech Medical Instruments Inc., Raleigh, NC) with a calibration check done by a mercury sphygmomanometer. After the 45‐min postexercise recovery period, the ambulatory BP monitor was programmed to obtain three ambulatory BP assessments for each waking hour and two for each sleeping hour over 19 h. We instructed the subjects to proceed with their normal daily activities and not to engage in formal exercise while wearing the monitor.…”

“…; Pescatello et al. ). These findings and FURIN's regulatory role in BP control make FURIN a biological plausible candidate gene to explore for associations with PEH.…”