Gene-environment interaction in the regulation of HDL: The hepatic lipase gene promoter polymorpism modulates the physical activity associated increase in HDL
HDL-C is an important protective factor for coronary heart disease. Physical activity raises HDL-C, although the effect varies among individuals. The hepatic lipase (HL) promoter polymorphism (HL-514C→T) is associated with HDL-C. This study addresses the question: is the relationship between physical activity and HDL-C altered by an individual’s HL promoter polymorphism genotype? Non-diabetic subjects from the San Luis Valley Diabetes Study provided a 7 day physical activity recall from which metabolic equivalents (METS) were calculated. Anthropomorphic measures and fasting blood for lipid and DNA analysis were also collected. Women were excluded if postmenopausal or taking estrogen, resulting in 248 Hispanic and 363 non-Hispanic White (NHW) subjects. The frequency of the HL-514T allele was 0.18 in NHW compared to 0.47 in Hispanics (p<0.001). Women had higher HDL-C than men (52±13 vs. 45±11, p<0.001). The HL-514T allele was associated with higher HDL-C in men (46±12 vs. 44±11 for HL-514CC, p<0.03), but not in women (51±13 vs. 52±13 for the HL-514CC, p=0.5). METS were positively related to HDL-C in both men and women(r=0.18, p=0.001; and r=0.20, p<0.01, respectively). Multivariate analysis showed a statistically significant interaction between METS and the HL-514 allele on HDL-C (p<0.001). That is, subjects with the HL-514T allele showed less of an effect of METS on HDL-C compared to HL-514CC (slope=0.01, p=0.08 vs. slope=0.03, p=0.005, respectively), after adjusting for age, sex, ethnicity, BMI, waist/hip ratio, and log triglyceride. BMI was also independently related to HDL-C (p<0.0001). Thus, in this free living rural community, the beneficial effects of physical activity on HDL-C are modulated by the hepatic lipase gene promoter polymorphism. Individuals with the HL-514T allele are more resistant to exercise associated higher HDL-C. The allele-specific effects of physical activity on HDL-C were independent of body fat and fat distribution. This suggests a genotype-specific targeted approach of exercise intervention to raise HDL and reduce coronary disease risk may be warranted.