FURINvariant associations with postexercise hypotension are intensity and race dependent

Abstract

FURIN is a proprotein convertase subtilisin/kexin enzyme important in pro‐renin receptor processing, and FURIN (furin, paired basic amino acid cleaving enzyme) variants are involved in multiple aspects of blood pressure (BP) regulation. Therefore, we examined associations among FURIN variants and the immediate blood pressure (BP) response to bouts of aerobic exercise, termed postexercise hypotension (PEH). Obese (30.9 ± 3.6 kg m−2) Black‐ (n = 14) and White‐ (n = 9) adults 42.0 ± 9.8 year with hypertension (139.8 ± 10.4/84.6 ± 6.2 mmHg) performed three random experiments: bouts of vigorous (VIGOROUS) and moderate (MODERATE) intensity cycling and control. Subjects were then attached to an ambulatory BP monitor for 19 h. We performed deep‐targeted exon sequencing with the Illumina TruSeq Custom Amplicon kit. FURIN genotypes were coded as the 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. After VIGOROUS over 19 h, as FURIN #MA increased in rs12917264 (P = 2.4E‐04) and rs75493298 (P = 6.4E‐04), systolic BP (SBP) decreased 30.4–33.7 mmHg; and in rs12917264 (P = 1.6E‐03) and rs75493298 (P = 9.7E‐05), diastolic BP (DBP) decreased 17.6–20.3 mmHg among Blacks only. In addition, after MODERATE over 19 h in FURIN rs74037507 (P = 8.0E‐04), as #MA increased, SBP increased 20.8 mmHg among Blacks only. Whereas, after MODERATE over the awake hours in FURIN rs1573644 (P = 6.2E‐04), as #MA increased, DBP decreased 12.5 mmHg among Whites only. FURIN appears to exhibit intensity and race‐dependent associations with PEH that merit further exploration among a larger, ethnically diverse sample of adults with hypertension.

A Systematically Assembled Signature of Genes to be Deep-Sequenced for Their Associations with the Blood Pressure Response to Exercise

“…Of the qualifying trials containing human genes in major BP regulatory pathways, we extracted 11 genes associated with the BP response to exercise under criteria 1 [33,34,35,36,37,38,39,40]; 18 genes associated with hypertension in GWAS under criteria 2 [41,42,43,44,45,46,47,48]; 28 genes associated with the BP response to pharmacotherapy under criteria 3 [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70]; 27 genes associated with physical activity and/or obesity in GWAS under criteria 4a [71,72,73,74,75,76,77,78,79,80,81,82,83,84,85]; and 29 genes associated with BP, physical activity, and/or obesity in non-GWAS under criteria 4b [86,87,88] displayed in Supplemental Digital Content (SDC) 1 Table S1. In addition, we included the 41 genes from our preliminary work that were reported to be associated with hypertension or the BP response to exercise or pharmacotherapy [27,28,29].…”

“…More recently, using newer genomic technology that emerged since our discovery phase candidate gene association studies, in a replication cohort we deep-sequenced the exons of genes contained on a prioritized signature of 41 genes identified from our earlier work combined with those from a systematic review of the literature of genes reported to be associated with hypertension or the BP response to exercise or pharmacotherapy using the Illumina TruSeq Custom Amplicon kit [27,28,29]. Even after adjustment for multiple testing, we found that 61% of the genes in the prioritized panel associated with the BP response to exercise.…”

“…We attributed the high proportion of significant BP-genotype associations that we found to the following methodological strategies we instituted [27,28,29]: a randomized control repeated measure design with subjects who were their own control; a focused inquiry of variants with a prioritized panel of genes obtained from a systematic review of the literature that reduced the search space within the genome; high throughput exon sequencing on functional gene regions; standardized protocols that included a closely monitored, well-controlled exercise exposure; and adjustment for multiple testing based on genetic variants exhibiting variability in the number of minor alleles and with unique genotypic values. This series of studies are proof of concept that a focused genomic inquiry on functional portions of genes based upon a systematic review of the literature is a time and cost-efficient way to investigate the genomic basis for the antihypertensive effects of exercise.…”

“…These a priori criteria were human genes in major BP regulatory pathways reported to be associated with: (1) the BP response to exercise; (2) hypertension in genome-wide association studies (GWAS); (3) the BP response to pharmacotherapy; (4a) physical activity and/or obesity, a major risk factor for hypertension as 80% of adults with hypertension are overweight to obese [32] in GWAS; and (4b) BP, physical activity, and/or obesity in non-GWAS from relevant reference searches of the authors’ files. We also included the genes from the prioritized signature of BP and exercise genes from our previous work [27,28,29].…”

“…More recently, we exploited advances in genomic technology that emerged since our discovery phase candidate gene association studies as well as other strategies to bolster our statistical power to detect genetic variants associated with the BP response to exercise in a replication cohort of subjects with hypertension whose characteristics resembled those from our earlier studies. In this series of studies, we deep-sequenced the exons of genes using the Illumina TruSeq Custom Amplicon kit (Catalog# FC-130-1001, Illumina, San Diego, CA, USA) on a prioritized signature of 41 BP and exercise genes that contained genes identified from our prior work in addition to those obtained from a systematic review of the literature of genes reported to be associated with hypertension or the BP response to exercise or pharmacotherapy [27,28,29]. After adjustment for multiple testing, despite the small sample size, we found variants in 61% of the 41 genes in the prioritized panel associated with the BP response to exercise.…”