Genetic Modifiers of Cardiorespiratory Fitness Response to Lifestyle Intervention

Abstract

Purpose 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. Methods 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. Results 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=1.9×10−5) and genotype-intervention interaction (P=4.8×10−3). 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=5.3×10−7), and genotype-treatment interaction (P=5.3×10−5). GRAIL pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis. Conclusions 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.

Cardiorespiratory Fitness and Gray Matter Volume in the Temporal, Frontal, and Cerebellar Regions in the General Population

“…In addition, CRF is not only affected by continuous aerobic physical activity but also by behavioral risk factors, genetics, and comorbid conditions. 40,41 Batouli and Saba 42 gave a good overview of the current literature about physical activity and CRF markers, but their conclusion that "at least eighty percent of the brain gray matter is modifiable by physical activity" cannot be supported by the findings from our well-powered and representative analyses.…”

Genetic risk variants for metabolic traits in Arab populations

“…Peter et al . report that the FKBP7 gene showed a significant association with intensive lifestyle intervention response among overweight/obese diabetic individuals not receiving beta-blocker medications38.…”

“…Interestingly, four of these seven genes (namely PGM5 regulated by rs11143005, NLRC5 by rs1800775, NOS2 by rs17716285, FKBP7 by rs10497520) have literature evidence for associations with metabolic traits2435363738 and thus these genes are potential candidate genes for further functional studies on processes relating to metabolic traits in this population.…”

A reverse genetics cell‐based evaluation of genes linked to healthy human tissue age

“…CD36 has been shown to contain RUNX-binding elements, and RUNX3 can repress CD36 expression in myeloid cells (38). Little is understood about the potential link of RUNX1 to age-related pathways, although it is a genomic mediator of adaptation to exercise (39, 40) and thus may be an example of a key determinant of age–gene–environmental interactions. Whether increased CD36 expression with aging is protective or damaging is unclear, but this change may be the result of reduced expression of RUNX transcription factors.…”