Genetic Modifiers of Cardiorespiratory Fitness Response to Lifestyle Intervention

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 10Molecular Cardiology Research Institute, Center for Translational Genomics, Tufts Medical Center and Tufts University, Boston, MA, USA.
Medicine and science in sports and exercise (Impact Factor: 3.98). 07/2013; 46(2). DOI: 10.1249/MSS.0b013e3182a66155
Source: PubMed


Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes (T2D) 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 T2D compared to 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 metabolic equivalent (MET) level, estimated using a treadmill test, in response to a one-year intervention in 3,899 participants.
We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with one-year METs response in ILI (0.19±0.04 MET less improvement per minor allele copy; P=1.9×10) and genotype-intervention interaction (P=4.8×10). In the chip-wide 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), and genotype-treatment interaction (P=5.3×10). GRAIL 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. f 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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Available from: Yao Yang, Jan 14, 2015
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