Identification of novel genetic variants associated with cardiorespiratory fitness

https://doi.org/10.1016/j.pcad.2020.02.001Get rights and content
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Abstract

Introduction

Low maximal oxygen uptake (VO2max) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. For other CVD risk factors, numerous genetic association studies have been performed, revealing promising risk markers and new therapeutic targets. However, large genomic association studies on VO2max are still lacking, despite the fact that VO2max has a large genetic component.

Methods

We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO2max in 3470 individuals (exploration cohort). Candidate SNPs from the exploration cohort were analyzed in a validation cohort of 718 individuals, in addition to 7 wild-card SNPs. Sub-analyses were performed for each gender. Validated SNPs were used to create a genetic score for VO2max. In silico analyses and genotype-phenotype databases were used to predict physiological function of the SNPs.

Results

In the exploration cohort, 41 SNPs were associated with VO2max (p < 5.0 ∗ 10−4). Six of the candidate SNPs were associated with VO2max also in the validation cohort, in addition to three wild-card SNPs (p < 0.05, in men, women or both). The cumulative number of high-VO2max-SNPs correlated negatively with CVD risk factors, e.g. waist-circumference, visceral fat, fat %, cholesterol levels and BMI. In silico analysis indicated that several of the VO2max-SNPs influence gene expression in adipose tissue, skeletal muscle and heart.

Conclusion

We discovered and validated new SNPs associated with VO2max and proposed possible links between VO2max and CVD. Studies combining several large cohorts with directly measured VO2max are needed to identify more SNPs associated with this phenotype.

Abbreviations and acronyms

ACTN3
alpha-actinin-3
ADRB3
beta-3 adrenergic receptor
APOA1
apolipoprotein A1
APOER2
apolipoprotein E receptor 2
BAHD1
Bromo adjacent homology domain containing 1
BMI
body mass index
CRP
C-reactive protein
CVD
cardiovascular disease
DNA
deoxyribonucleic acid
EDN1
endothelin 1
ERα
estrogen receptor alpha
GWAS
genome-wide association studies
HDL
high-density lipoprotein
HUNT
Nord-Trøndelag Health Study
IGF2
insulin-like growth factor 2
KCNQ1
potassium voltage-gated channel subfamily Q member 1
LDL
low-density lipoprotein
LDLR
low density lipoprotein receptor
LXR
liver X receptor
MAF
minor allele frequency
MET
metabolic equivalent
MYLIP
myosin regulatory light chain interacting protein
MYOCD
myocardin
PROX1
Prospero homeobox protein 1
SNP
single-nucleotide polymorphism
VIP
vasoactive intestinal peptide
VIPR2
vasoactive intestinal peptide receptor 2
VLDLR
very low density lipoprotein receptor
VO2max
maximal oxygen uptake

Keywords

Maximal oxygen uptake
Genetics
Cardiovascular disease risk

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Statement of Conflict of Interest: see page 348.