Women who reported physical activity levels above the median of 8.8 MET-hours/wk had, on average, a lower baseline body mass index (BMI), lower TG levels, higher levels of HDL-C and ApoA1, and a lower prevalence of self-reported diabetes and hypertension (). Post menopausal hormone use and moderate alcohol use was also more common amongst more active women.
Characteristics of Study Participants According to Physical Activity Levels
The SNPs associated with HDL-C levels at a genome-wide level of statistical significance and their unadjusted P-values for interaction with the median level of physical activity (8.8 MET-hrs/week) are displayed in Supplementary Table 1
, sorted by chromosomal position. Evidence of effect modification was observed for 8 SNPs in 4 genes, including 2 SNPs at LPL
(8q21), 3 at LIPC
(15q22), 2 at CETP
(16q13), and 1 at LIPG
(18q45). The SNPs with the smallest interaction P-value at each locus were rs10096633 (LPL
; P-interaction=0.006), rs1800588 (LIPC
; P-interaction=0.01), rs1532624 (CETP
; P-interaction=0.008) and rs4939883 (LIPG
; P-interaction=0.03). The absolute difference (SE) in HDL-C level per copy of each significant allele ranged from 1.098 (0.193) for rs4939883 in LIPG
(minor allele frequency (MAF) = 0.17) to 3.067 (0.146) for rs1532624 in CETP
(MAF = 0.43). We did not observe evidence of effect modification for other SNPs with similar MAF and effect sizes (Supplementary Table 1
). None of the 5 SNPs identified in a sensitivity analysis using physical activity adjusted HDL-C met the pre-specified criteria for evidence of effect modification (Supplementary Table 2
Mean (±SD) HDL-C by genotype and increase in HDL-C per copy of the minor alleles at significant SNPs within the LPL, LIPC, CETP
genes in all women and in women stratified by median levels of physical activity are displayed in . As shown, we observed a smaller per-allele increase in HDL-C for rs10096633 at LPL
among active women (1.0 mg/dL per copy) than among inactive women (2.1 mg/dL per copy, P-interaction=0.004). By contrast, for rs1532624 at CETP
and rs1800588 at LIPC
, we observed a larger increase in HDL-C levels per copy of the minor allele in active women than in inactive women (P-interaction= 0.04 and 0.02, respectively). While our initial test for interaction suggested that the effect of rs4939883 at LIPG
on HDL-C levels was modified by physical activity, this effect was no longer statistically significant in the fully adjusted model. Similar results were seen for the SNPs in LPL
, and CETP
when using an alternative physical activity cutpoint (Supplementary Table 3
). The distribution of HDL-C levels stratified by genotype and physical activity level are presented in the Supplementary Figure
. The proportion of variance in HDL-C explained by the physical activity-genotype interaction was 0.03% for rs10096633 in LPL
, 0.01% for rs1800588 in LIPC
, and 0.03% for rs1532624 in CETP
. By comparison, adding each of SNP individually to adjusted models explained an additional 0.27% (rs10096633), 0.58% (rs1800588), or 1.99% (rs1532624) of the variance in HDL-C. In sensitivity analyses using a P-value threshold corrected for the number of genes analyzed (P<0.0056), evidence of interaction remained statistically significant only for rs10096633 in LPL
. When we restricted our analysis to women who had been fasting for at least 8 hours at the time of blood collection our observations did not differ substantially.
Mean HDL-C (mg/dl) Levels per copy of the Minor Allele at Significant SNPs in the Entire Cohort and Across Median levels of Physical Activity
We observed similar associations between the above SNPs and ApoA1 levels (). As seen with HDL-C, the observed per-allele increase in ApoA1 for rs10096633 at LPL was greater among inactive women (interaction<0.001). Copies of the minor allele at rs1532624 (CETP) and rs1800588 (LIPC) were associated with a greater increases in ApoA1 levels amongst active women, compared to inactive women (P-interaction=0.02 and 0.09, respectively).
Mean ApoA1 (mg/dl) Levels per copy of the Minor Allele at Significant SNPs in the Entire Cohort and Across Median levels of Physical Activity
Higher HDL-C levels were observed among women with the beneficial as compared with deleterious genotype at rs10096633 in LPL (55.08 vs. 53.33mg/dL, P<0.0001), rs1800588 at LIPC (55.17 vs. 52.87mg/dL, P<0.0001), and rs1532624 at CETP (54.99 vs. 51.26 mg/dL, P<0.0001). However, only women who carried at least one copy of the minor allele at CETP had a reduced risk of MI (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.57–0.92; P=0.009) after adjusting for age, body mass index, diabetes, blood pressure, current smoking, and total cholesterol. Women with a beneficial genotype at rs10096633 (LPL) or rs1800588 (LIPC) were not at reduced risk of MI (LPL-HR 0.81, 95% CI 0.61–1.09, P=0.16; LIPC-HR 1.11, 95% CI 0.87–1.41, P=0.39).
The fully adjusted risks of MI for each of the four categories of genotype score and activity level are presented in . As shown in , compared to inactive women with a deleterious genotype at LPL, active carriers of at least one copy of the minor allele at rs10096633 were at reduced risk of MI (HR 0.51, 95% CI 0.30–0.86; P=0.01). By contrast, inactive women with the beneficial genotype at LPL were not at reduced risk of MI (HR 1.13, 95% CI 0.79–1.61; P=0.50; P-interaction = 0.007). The effect of physical activity on MI risk did not appear to be modified by genotype score at rs1800588 (LIPC) (P-interaction = 0.71, ). Finally, the reduction in risk associated with a beneficial genotype at rs1532624 at CETP appeared to be similar in active and inactive women, regardless of physical activity level (P-interaction = 0.71, ).
Figure 1 Risk of incident myocardial infarction according to categories of leisure-time physical activity level and genotype score at the LPL (1A), LIPC (1B), and CETP (1C) loci. Women with at least one copy of the minor allele at each locus were defined as having (more ...)