Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry

Circ Cardiovasc Genet. 2011 Feb;4(1):74-80. doi: 10.1161/CIRCGENETICS.110.957290. Epub 2011 Jan 20.


Background: Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain.

Methods and results: In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (P<5×10(-8)) with HDL-C levels and sought evidence of effect modification according to levels of physical activity. Physical activity modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at lipoprotein lipase (LPL), rs1800588 at hepatic lipase (LIPC), and rs1532624 at cholesteryl ester transfer protein (CETP) (each P-interaction<0.05). The per-minor-allele increase in HDL-C for rs1800588 at LIPC and rs1532624 at CETP was greater in active than inactive women, whereas the reverse was observed for rs10096633 at LPL. Minor-allele carrier status at the LPL SNP was associated with a reduced risk of myocardial infarction in active (hazard ratio, 0.51; 95% confidence interval 0.30-0.86) but not among inactive women (hazard ratio 1.13; 95% confidence interval 0.79 to 1.61; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of myocardial infarction regardless of activity level (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P-interaction=0.71). No association between LIPC SNP carrier status and myocardial infarction risk was noted.

Conclusions: The effects of common variants in the LPL, LIPC, and CETP genes on HDL-C levels are modified by physical activity. For a common variant in LPL, the impact on myocardial infarction varied by activity level, whereas the effects of a common variant in CETP on myocardial infarction risk did not.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Apolipoprotein A-I / blood
  • Cholesterol Ester Transfer Proteins / genetics*
  • Cholesterol, HDL / blood
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Leisure Activities
  • Lipase / genetics*
  • Lipoprotein Lipase / genetics*
  • Middle Aged
  • Motor Activity*
  • Myocardial Infarction / blood
  • Myocardial Infarction / genetics*
  • Polymorphism, Single Nucleotide / genetics*
  • Risk Factors
  • Whites / genetics*


  • Apolipoprotein A-I
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Cholesterol, HDL
  • LIPC protein, human
  • Lipase
  • LPL protein, human
  • Lipoprotein Lipase