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Med Sci Sports Exerc. 2014 Feb;46(2):302-11. doi: 10.1249/MSS.0b013e3182a66155.

Genetic modifiers of cardiorespiratory fitness response to lifestyle intervention.

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1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY; 2Center for Statistical Sciences, Brown University, Providence, RI; 3Department of Medicine, University of Texas Medical Branch, Galveston, TX; 4Department of Health and Physical Activity, Physical Activity and Weight Management Research Center, University of Pittsburgh, Pittsburgh, PA; 5Weight Control and Diabetes Research Center, Department of Psychiatry and Human Behavior, The Miriam Hospital and Brown Medical School, Providence, RI; 6Translational Metabolism Unit, Diabetes Research Center, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX; 7Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA; 8Diabetes Research Center, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA; 9Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC; and 10Molecular Cardiology Research Institute, Center for Translational Genomics, Tufts Medical Center and Tufts University, Boston, MA.



Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes risk and delays disease progression. We hypothesized that genetic variants modify fitness response to an intensive lifestyle intervention (ILI) in the Action for Health in Diabetes (Look AHEAD) randomized clinical trial, aimed to detect whether ILI will reduce cardiovascular events in overweight/obese subjects with type 2 diabetes compared with a standard of care.


Polymorphisms in established fitness genes and in all loci assayed on the Illumina CARe iSelect chip were examined as predictors of change in MET level, estimated using a treadmill test, in response to a 1-yr intervention in 3899 participants.


We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with 1-yr METs response in ILI (0.19 ± 0.04 MET less improvement per minor allele copy; P = 1.9 × 10(-5)) and genotype-intervention interaction (P = 4.8 × 10(-3)). In the chipwide analysis, FKBP7 rs17225700 showed a significant association with ILI response among subjects not receiving beta-blocker medications (0.47 ± 0.09 METs less improvement; P = 5.3 × 10(-5)) and genotype-treatment interaction (P = 5.3 × 10(-7)). The Gene Relationships Among Implicated Loci pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis.


This is the first study to identify genetic variants associated with fitness responses to a randomized lifestyle intervention in overweight/obese diabetic individuals. RUNX1 and FKBP7, involved in erythropoesis and muscle protein synthesis, respectively, are related to change in cardiorespiratory fitness in response to exercise.

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