Identification of novel genetic variants associated with cardiorespiratory fitness.

INTRODUCTION

Low maximal oxygen uptake (VO) 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 VO are still lacking, despite the fact that VO has a large genetic component.

METHODS

We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO 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 VO. 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 VO (p < 5.0 ∗ 10). Six of the candidate SNPs were associated with VO 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-VOSNPs 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 VO-SNPs influence gene expression in adipose tissue, skeletal muscle and heart.

CONCLUSION

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