Abstract P461: Genome-wide Analysis in Sedentary Adults of Non-completion of a Controlled Exercise Intervention
Jiang, R; Huffman, KM; Hauser, E; Hubal, M; Slentz, C; Johnson, J; Babyak, M; Williams, R; Siegler, IC; Kraus, WE
Published in: Circulation
A wide range of health benefits of exercise have been documented in clinical lifestyle medicine. However, many individuals fail to complete or maintain an exercise program. We hypothesized that this behavior has biological underpinnings. Thus, we conducted analyses of multi-omic data obtained from genomic, transcriptomic and metabolomic data specific to subjects (n=603) initiating a well-characterized exercise training trial (STRRIDE-Study of a Targeted Risk Reduction Intervention through Defined Exercise) to understand the biology of non-completion. GWAS detected the strongest evidence of association with non-completion was at SNP rs722069 (P = 2.2 х 10
, OR=2.23, T/C, risk allele =C) on chromosome 16, with other 8 SNPs in a linkage disequilibrium block (pairwise R
> 0.74). These SNPs were eQTLs of the
and
genes in skeletal muscle tissue in GTEx portal. In a subset of the STRRIDE sample, the C allele of rs722069 was associated with lower pre-exercise skeletal muscle expression of
(P < 0.016) using Affymetrix platform (n=37). This was further replicated (P=0.017) in another set of skeletal muscle expression data using the Illumina gene expression array (n=67). The C allele was associated with lower pre-exercise skeletal muscle concentrations of C2- and C3-acylcarnitines (P < 0.03) - the incomplete oxidation products of fatty acid and amino acid metabolism. Lower
skeletal muscle expression was also related to the lower C2- and C3-acylcarnitine concentrations in skeletal muscle (
< 0.05) before exercise. Rs722069 variants were not related to maximal oxygen uptake and insulin sensitivity in the individuals completing the exercise intervention. The tests of glucose and lipids levels associated with the genetic variants in this LD block are ongoing. To further understand the systemic genetics and biology of non-completion,
functional analysis for the genes in this region such as
is also under way. Our results imply that non-completion is genetically moderated through differential gene expression and metabolic pathways in skeletal muscle. Impaired mitochondrial energetics in skeletal muscle may be partly responsible for non-completion. Individual genetic traits may allow development of a biomarker-approach to identify individuals that would benefit from more intensive counseling to maintain exercise programs.
