Causal associations between cardiorespiratory fitness and type 2 diabetes

• Published in: Nature communications Vol. 14; no. 1; pp. 3904 - 13
• Main Authors: Cai, Lina, Gonzales, Tomas, Wheeler, Eleanor, Kerrison, Nicola D., Day, Felix R., Langenberg, Claudia, Perry, John R. B., Brage, Soren, Wareham, Nicholas J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308/174; 692/308/2056; 692/499; 692/699/2743/137/773; Adipose tissue; Biological activity; Brain natriuretic peptide; Cardiac muscle; Cardiorespiratory fitness; Cardiorespiratory Fitness - physiology; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Fitness; Globulins; Growth factors; Heart rate; Hepatocyte growth factor; Humanities and Social Sciences; Humans; multidisciplinary; Muscle contraction; Muscles; Obesity; Proteomics; Risk; Risk Factors; Science; Science (multidisciplinary); Sex hormones
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38234-w

Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6 , that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention. Being fit has been linked to a lower risk of type 2 diabetes, but it is unclear whether this relationship is causal. Using large scale studies with genetic data and measurements of cardiorespiratory fitness, the authors show evidence that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity.