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

Linda S Pescatello; Elizabeth D Schifano; Garrett I Ash; Gregory A Panza; Lauren M L Corso; Ming-Hui Chen; Ved Deshpande; Amanda Zaleski; Burak Cilhoroz; Paulo Farinatti; Beth A Taylor; Rachel J O'Neill; Paul D Thompson

doi:10.14814/phy2.13510

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

Physiol Rep. 2017 Nov;5(22):e13510. doi: 10.14814/phy2.13510.

Authors

Linda S Pescatello^{1

2}, Elizabeth D Schifano³, Garrett I Ash⁴, Gregory A Panza^{5

6}, Lauren M L Corso⁵, Ming-Hui Chen³, Ved Deshpande³, Amanda Zaleski^{5

6}, Burak Cilhoroz⁵, Paulo Farinatti⁷, Beth A Taylor^{5

6}, Rachel J O'Neill^{2

8}, Paul D Thompson⁶

Affiliations

¹ Department of Kinesiology, University of Connecticut, Storrs, Connecticut Linda.Pescatello@uconn.edu.
² Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut.
³ Department of Statistics, University of Connecticut, Storrs, Connecticut.
⁴ School of Nursing, Yale University, New Haven, Connecticut.
⁵ Department of Kinesiology, University of Connecticut, Storrs, Connecticut.
⁶ Department of Preventive Cardiology, Hartford Hospital, Hartford, Connecticut.
⁷ Department of Physical Activity Sciences, Rio de Janeiro State University, Rio de Janeiro, Brazil.
⁸ Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut.

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.

Keywords: Blood Pressure; Exercise; Hypertension; Polymorphism.

MeSH terms

Adolescent
Adult
Black or African American / genetics
Blood Pressure
Exercise*
Exons
Female
Humans
Male
Middle Aged
Nitric Oxide Synthase Type III / genetics*
Polymorphism, Single Nucleotide*
Post-Exercise Hypotension / ethnology
Post-Exercise Hypotension / genetics*
Post-Exercise Hypotension / physiopathology
White People / genetics

Substances

NOS3 protein, human
Nitric Oxide Synthase Type III

Abstract

MeSH terms

Substances

Grants and funding