Abstract
Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48–0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1711-1721 |
| Number of pages | 11 |
| Journal | Nature Medicine |
| Volume | 30 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2024 |
Funding
R.V.S. and A.S.P. have applied for a patent related to the findings in this manuscript. R.V.S. is supported in part by grants from the National Institutes of Health and the American Heart Association. In the past 12 months, R.V.S. has served for a consultant for Amgen and Cytokinetics. R.V.S. is a co-inventor on a patent for ex-RNAs signatures of cardiac remodeling and a pending patent on proteomic signatures of fitness and lung and liver diseases. V.L.M. has received grant support from Siemens Healthineers, NIDDK, NIA, NHLBI and AHA. V.L.M. has received other research support from NIVA Medical Imaging Solutions. V.L.M. owns stock in Eli Lilly, Johnson & Johnson, Merck, Bristo-Myers Squibb, Pfizer and stock options in Ionetix. V.L.M. has received research grants and speaking honoraria from Quart Medical. G.D.L. has hospital-based research agreements with from National Institutes of Health R01-HL 151841, R01-HL131029, R01-HL159514, U01HL160278, American Heart Association 15GPSGC-24800006 and SFRN for research involving exercise omics, and has received consulting fees from American Regent, Amgen, Cytokinetics, Boehringer Ingelheim, and Edwards and has received royalties from UpToDate for scientific content authorship related to exercise physiology. M.N. has received speaking honoraria from Cytokinetics. The remaining authors declare no competing interests. A.S.P. is supported by the AHA (20SFRN35120123). J.M.R. is supported by the National Institutes of Health (NIH) (K23HL150327). R.V.S. is supported by grants from the American Heart Association (AHA) and NIH. M.N. is supported by NIH (R01HL156975, R01HL131029) and by a Career Investment Award from the Department of Medicine, Boston University School of Medicine. R.E.G. and M.A.S. were funded by R01NR019628. T.T., K.A.W., and L.F. are supported by the National Institute on Aging\u2019s Intramural Research Program. P.R. is supported by the John S. LaDue Memorial Fellowship at Harvard Medical School. Q.S.W. is supported by the NIH (R01HL140074). M.Y.M. was supported by the NIH (K23HL171855). B.C. is supported by an Early Career Investigator Grant from the American Lung Association. The BLSA study was funded by the National Institute on Aging\u2019s Intramural Research Program. Proteomics in CARDIA were funded by a grant to R.K. (R01HL122477). CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (75N92023D00002 and 75N92023D00005), Northwestern University (75N92023D00004), University of Minnesota (75N92023D00006) and Kaiser Foundation Research Institute (75N92023D00003). This manuscript has been reviewed by CARDIA for scientific content. Exercise testing in CARDIA was funded by a grant to S.S. and B. Sternfeld (R01HL078972). The Fenland Study is funded by the UK Medical Research Council, with proteomic assessment funded by Somalogic; Investigators T.G., N.J.W. and S.B. received support from the UK Medical Research Council (MC_UU_00006/1, MC_UU_00006/4) as well as the National Institute for Health and Care Research Cambridge Biomedical Research Centre (IS-BRC-1215-20014). The HERITAGE study was supported by several grants from the NHLBI (R01HL45670, R01HL47317, R01HL47321, R01HL47323 and R01HL47327).
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology