Genetic Variation in Acid Ceramidase Predicts Non-completion of an Exercise Intervention

Abstract

Genetic variation is associated with a number of lifestyle behaviours; it may be associated with adherence and individual responses to exercise training. We tested single nucleotide polymorphisms (SNPs) in the acid ceramidase gene (ASAH1) for association with subject adherence and physiologic benefit with exercise training in two well-characterised randomised, controlled 8-month exercise interventions: STRRIDE I (n = 239) and STRRIDE II (n = 246). Three ASAH1 non-coding SNPs in a linkage disequilibrium block were associated with non-completion: rs2898458(G/T), rs7508(A/G), and rs3810(A/G) were associated with non-completion in both additive (OR = 1.8, 1.8, 2.0; P < 0.05 all) and dominant (OR = 2.5, 2.6, 3.5; P < 0.05 all) models; with less skeletal muscle ASAH expression (p < 0.01) in a subset (N = 60); and poorer training response in cardiorespiratory fitness (peak VO₂ change rs3810 r² = 0.29, P = 0.04; rs2898458 r² = 0.29, P = 0.08; rs7508 r² = 0.28, p = 0.09); and similar in direction and magnitude in both independent exploratory and replication studies. Adherence to exercise may be partly biologically and genetically moderated through metabolic regulatory pathways participating in skeletal muscle adaptation to exercise training.

Keywords: STRRIDE; behavioural lifestyle interventions; ceramide; exercise adherence; metabolism.

Figure 1

Linkage disequilibrium plot for Acid Ceramidase SNPs. SNPs assessed in the current study are shown above the linkage disequilibrium (LD) plots for genotype in white subjects (left) and black subjects (right) participating in either STRRIDE I or STRRIDE II. Results given are r²-values for association. The intensity of the block is proportional to the association between two variants. SNPs rs2898458, rs7508, and rs3810 as well as rs2427746 and rs1049874 are shown to be in LD(r² > 0.6) in whites (n = 371). Only rs2898458 and rs3810 are in LD (r² > 0.6) in blacks (n = 114).

Figure 2

Effect of rs3810 genotype on completion rate in STRRIDE II. Percent of subjects in STRRIDE II completing (grey filled bars) and failing to complete (open bars) the study intervention by rs3810 genotype (GG genotype n = 87, GT genotype n = 114, TT genotype n = 38; when controlled for race, gender, and exercise group effects, additive model OR = 2.0, p = 0.01 and dominant model OR = 3.5, p = 0.005). These findings were similar to those for rs2898458 and rs7508 (data not shown).

Figure 3

Genotype effect on odds of failure to complete study by SNP in STRRIDE II vs. STRRIDE I. Additive model odds ratios for risk of study non-completion for each ASAH SNP for STRRIDE I (x axis) and STRRIDE II (y axis). Two SNPs significantly increased the odds of failure to complete both STRRIDE II and STRRIDE I: rs2898458 and rs3810. SNP rs7508 significantly increased the odds of study non-completion in STRRIDE II.

Figure 4

Improvement in peak oxygen consumption (peak VO₂) with exercise training by rs3810 genotype. Improvement in peak VO₂ (mL/kg/min), measured as the difference in peak VO₂ before and after an exercise intervention, compared to rs3810 genotype. STRRIDE I and STRRIDE II datasets were combined for the analysis (GG genotype n = 168, GT genotype n = 207, TT genotype n = 90). The rs3810 genotype significantly predicted change in peak VO₂ (p = 0.0185), despite the fact that some groups differed in the intensity of the training stimulus.

Figure 5

mRNA Expression of ASAH1 Stratified by rs3810 Genotype. Two distinct Affymetrix probe sets indicated that ASAH1 mRNA expression is significantly different by rs3810 genotype using either full (p = 0.006–0.007) or dominant (p = 0.01–0.02) models, using sex and race as covariates. Females are represented by rectangles and males are represented by circles. TT individuals demonstrated 1.3–1.4 times lower skeletal muscle acid ceramidase expression than did GG individuals at baseline.