Genomic and transcriptomic predictors of triglyceride response to regular exercise

AIM: We performed genome-wide and transcriptome-wide profiling to identify genes and single nucleotide polymorphisms (SNPs) associated with the response of triglycerides (TG) to exercise training. METHODS: Plasma TG levels were measured before and after a 20-week endurance training programme in 478 white participants from the HERITAGE Family Study. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. Affymetrix HG-U133+2 arrays were used to quantitate gene expression levels from baseline muscle biopsies of a subset of participants (N=52). Genome-wide association study (GWAS) analysis was performed using MERLIN, while transcriptomic predictor models were developed using the R-package GALGO. RESULTS: The GWAS results showed that eight SNPs were associated with TG training-response (DeltaTG) at p<9.9x10-6, while another 31 SNPs showed p values <1x10-4. In multivariate regression models, the top 10 SNPs explained 32.0% of the variance in DeltaTG, while conditional heritability analysis showed that four SNPs statistically accounted for all of the heritability of DeltaTG. A molecular signature based on the baseline expression of 11 genes predicted 27% of DeltaTG in HERITAGE, which was validated in an independent study. A composite SNP score based on the top four SNPs, each from the genomic and transcriptomic analyses, was the strongest predictor of DeltaTG (R2=0.14, p=3.0x10-68). CONCLUSIONS: Our results indicate that skeletal muscle transcript abundance at 11 genes and SNPs at a number of loci contribute to TG response to exercise training. Combining data from genomics and transcriptomics analyses identified a SNP-based gene signature that should be further tested in independent samples.