Physical activity may modify high genetic risk for CVD

Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease: Longitudinal Analyses in the UK Biobank Study

Literature - Tikkanen E, Gustafsson S, Ingelsson E, et al. - Circulation 2018: published online ahead of print

Introduction and methods

Physical exercise is a cost-effective method for CVD prevention, but fitness and physical activity are difficult to measure accurately and consistently on a large scale [1,2]. Additionally, it is not clear to which extent exercise can compensate the genetic CVD risk.

In this analysis of the UK Biobank, the associations of fitness and physical activity with incident CVD and all-cause death were evaluated, and it was assessed whether these associations are modified by genetic risk. For this purpose, objective and subjective measures of fitness and physical activity together with information of CVD risk factors and genomics in relation to prospective CVD disease events and all-cause death were analyzed, in 502,635 individuals.

The UK Biobank [3] is a longitudinal cohort study that enrolled more than 500,000 individuals aged 40-69 years between 2006 and 2010. The measures of fitness and physical activity were grip strength, total physical activity by means of the short form of the IPAQ questionnaire [4], and cardiorespiratory fitness (CRF), assessed with net oxygen consumption [5]. Available genome-wide genetic data of 468,095 individuals was used and Genetic Risk Score (GRS) for CHD and AF was calculated as the weighted sum of the risk alleles by using effect sizes from the reference genome-wide association study as weights [6,7]. The disease outcomes were coronary heart disease (CHD), stroke, heart failure (HF), atrial fibrillation (AF), and death. The median follow-up was 6.1 years (interquartile range: 5.4–6.8 years).

Main results

  • After adjustment for age, gender, and region, there were inverse associations between grip strength and all outcomes (HRs between 0.59 for HF and 0.90 for hemorrhagic stroke).
  • Physical activity assessed with an accelerometer had the strongest inverse association with all-cause death when compared with all other measures (HR: 0.52; 95%CI: 0.46–0.58).
  • Physical activity assessed with the IPAQ questionnaire had a modest inverse association with all-cause death (HR: 0.83; 95%CI: 0.82–0.84).
  • The correlation of accelerometer and IPAQ was modest (R=0.20), indicating substantial measurement inaccuracy in self-reported physical activity.
  • Cardiorespiratory fitness (CRF) was inversely associated with all CVD events, except hemorrhagic stroke. The strongest associations were observed for HF (HR: 0.56; 95%CI: 0.49–0.65) and AF (HR: 0.60; 95%CI: 0.56–0.65).
  • Higher grip strength and CRF were associated with lower risk of incident CHD and AF in each GRS group (Ptrend <0.001 in each genetic risk category).
  • In a subgroup of individuals at high genetic risk, those with high CRF had a 49% lower risk for CHD (HR: 0.51; 95%CI: 0.38–0.69) and a 60% lower risk for AF (HR: 0.40; 95%CI: 0.30–0.55), compared with those who had a low CRF. High grip strength was associated with lower risk for CHD (HR, 0.69; 95%CI, 0.62–0.75) and AF (HR, 0.61; 95% CI, 0.56–0.67), compared with those at low grip strength.
  • IPAQ-physical activity showed inverse associations with CHD in the lowest and highest GRS group (Ptrend=0.007 and Ptrend=0.003, respectively) and with AF in the intermediate and highest GRS group (Ptrend <0.001 and Ptrend =0.004, respectively), but the inverse patterns of associations were more modest than for grip strength and CRF.


In a large population based analysis, different measures of fitness and physical activity were inversely associated with future CVD events and all-cause death. Among those at high, intermediate, or low genetic predisposition for CHD and AF, there was a graded inverse association with these parameters among each stratum of genetic risk, suggesting that elevated genetic risk for CVD can be compensated for by exercise.


1. Timpka S, Petersson IF, Zhou C, et al. Muscle strength in adolescent men and risk of cardiovascular disease events and mortality in middle age: a prospective cohort study. BMC Med. 2014;12:62.

2. Andersen K, Rasmussen F, Held C, et al. Exercise capacity and muscle strength and risk of vascular disease and arrhythmia in 1.1 million young Swedish men: cohort study. BMJ.2015;351:h4543.

3. UK Biobank. https:// Accessed January 10, 2017.

4. International Physical Activity Questionnaire. Accessed January 10, 2017.

5. Swain DP. Energy cost calculations for exercise prescription: an update. Sports Med. 2000;30:17–22.

6. Nikpay M, Goel A, Won HHA, et al. A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015;47:1121–1130.

7. AFGen Consortium, Metastroke Consortium of the ISGC, Neurology Working Group of the Charge Consortium. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet. 2017; 49:946–952.

Find this article online at Circulation

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