Kjaergaard Alisa D, Ellervik Christina, Jessen Niels, Lessard Sarah J
Steno Diabetes Center Aarhus, Aarhus University Hospital, 8200 Aarhus, Denmark.
Joslin Diabetes Center, Boston, MA 02115, USA.
J Clin Endocrinol Metab. 2025 Apr 22;110(5):1451-1459. doi: 10.1210/clinem/dgae393.
Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality.
We investigated the causality and directionality of the associations of VO2max with body composition, physical activity, diabetes, performance enhancers, and longevity.
Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional 2-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO2max) was estimated from a submaximal cycle ramp test (N ≈ 70 000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg).
Genetically predicted higher (per 1 SD increase) body fat percentage was associated with lower VO2max (β = -0.36; 95% CI: -0.40, -0.32, P = 6 × 10-77). Meanwhile, genetically predicted higher appendicular lean mass (β = 0.10; 95% CI: 0.08 to 0.13), physical activity (β = 0.29; 95% CI: 0.07 to 0.52), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (all P < .01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max showed no associations.
Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO2max is not causally associated with T2D or longevity.
心肺适能通常通过最大摄氧量（VO2max）来评估，已成为发病率和死亡率的重要预测指标。
我们研究了VO2max与身体成分、体力活动、糖尿病、性能增强剂和长寿之间关联的因果关系和方向性。
利用公开可得的最大规模全基因组关联研究的汇总统计数据，我们进行了一项双向双样本孟德尔随机化（MR）研究。双向MR检验方向性，并估计总因果效应，而多变量MR（MVMR）估计独立因果效应。心肺适能（VO2max）通过次极量自行车递增负荷试验（N≈70000）进行估计，并按总体重进行标度，在额外分析中按去脂体重进行标度（毫升/分钟/千克）。
遗传预测的较高（每增加1个标准差）体脂百分比与较低的VO2max相关（β = -0.36；95%可信区间：-0.40，-0.32，P = 6×10-77）。同时，遗传预测的较高上肢瘦体重（β = 0.10；95%可信区间：0.08至0.13）、体力活动（β = 0.29；95%可信区间：0.07至0.52）和性能增强剂（男性的空腹胰岛素、血细胞比容和游离睾酮）均与VO2max呈正相关（所有P < 0.01）。糖尿病的遗传易感性对VO2max无影响。MVMR显示体脂百分比、上肢瘦体重、体力活动和血细胞比容对VO2max有独立因果效应，以及体脂百分比和2型糖尿病（T2D）对长寿有独立因果效应。遗传预测的VO2max未显示出关联。
良好的身体成分、体力活动和性能增强剂可改善心肺适能。尽管VO2max是死亡率的有力预测指标，但它与T2D或长寿无因果关联。
