The Health Outcome

Heart disease is the leading cause of death in the United States, accounting for 30% of deaths in the U.S. in 2000 (1). Over 6 million hospitalizations each year are due to cardiovascular disease, which is also a leading cause of premature, permanent disability in the U.S. workforce (2).

Cardiovascular disease has a multifactorial etiology with behavioral, environmental and genetic influences. Modifiable risk factors include high blood pressure, cigarette smoking, elevated cholesterol (total and low density lipoprotein), diabetes, obesity, environmental tobacco smoke exposure, and physical inactivity.

Hundreds of genes have been proposed as candidates for cardiovascular diseases, focusing on components of lipid metabolism, blood pressure regulation, hemostasis, thrombosis, obesity, insulin signaling and diabetes, and inflammation (3).

Hepatic lipase is a key rate-limiting enzyme in lipid and lipoprotein metabolism that is modified by exercise in some but not all subjects. A common polymorphism in the hepatic lipase gene (LIPC-480 C>T) is associated with differential effects of physical activity on HDL cholesterol levels, and the T allele of this polymorphism has been associated with increased risk of coronary heart disease (CHD). The mechanism by which this polymorphism promotes CHD is not known.

This study examines the association between a common polymorphism in the hepatic lipase gene (LIPC-480 C>T) and physical activity on incidence of CHD in a prospective, population-based cohort study (4).

The Finding

Hokanson et al. have reported that the TT genotype of the hepatic lipase LIPC-480 C>T polymorphism increased susceptibility to CHD events among subjects who were sedentary or engaged in vigorous physical activity less than three days per week for 20 minutes (4). However, there was no observed effect of the TT genotype among subjects who were vigorously active.

Subjects were 397 Hispanics and 569 non-Hispanic whites aged 20-74 years at age of recruitment into a population-based prospective cohort study of diabetes during 1984-1992 in the rural San Luis Valley, Colorado (overall 65% final participation rate). Subjects were followed through 1998 for occurrence of CHD events (heart attack, electrocardiogram major Q-wave abnormality, or death from acute, subacute, or chronic heart disease). Only 2% were lost to follow-up. Physical activity was determined at baseline by structured interview; vigorous activity was defined as any activity subjects considered strenuous or caused fatigue, increased heart rate, or sweating. LIPC-480 T allele frequency was higher in Hispanics (47%) than in non-Hispanic whites (19%) (p<0.001), but CHD risk by genotype was independent of ethnicity.

Frequency of the TT genotype was 19% for subjects who had a CHD event (n=91) compared to 10% for CHD-free subjects (p=0.04). Overall cumulative survival (free of CHD) was 54% for the TT genotype vs. 76% and 80% for CT and CC genotypes, respectively. Similar survival curves by genotype were observed stratified by ethnicity. In a Cox proportional hazards model controlling for sex, cholesterol, HDL cholesterol, hypertension, diabetes, and ethnicity, hazard ratios (95% confidence intervals) were: 0.88 (0.54, 1.44) for subjects with CC/CT genotype and vigorously active; 0.52 (0.12, 2.19) for those with TT and vigorously active; and 2.58 (1.39, 4.77) for those with TT and sedentary or moderately active (reference group was subjects with CC/CT genotype who were sedentary or moderately active).


Public Health Implications

The estimated fraction of CHD events occurring in the study cohort from the combination of LIPC-480 TT genotype and lack of vigorous physical activity was 11%. Less than 40% of the study cohort reported participating in vigorous physical activity. Physical activity should be promoted regardless of LIPC genotype, and particularly for persons with family history of CHD and other traditional CHD risk factors. Additional studies are needed to elucidate the role of hepatic lipase polymorphisms on lipid levels and subsequent CHD risk, possible interactions with other candidate genes for lipid metabolism, and the potential modifying role of vigorous physical activity on lipid metabolism in presence and absence of polymorphisms of candidate lipid metabolism genes (e.g., does exercise decrease levels of remnant lipoproteins, and subsequently increase coronary flow reserve in subjects with genetic susceptibility to these abnormalities?).

References

1. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the Unitetd States, 2000. JAMA 2004;291:1238-1246.
2.  http://www.cdc.gov/nccdphp/publications/AAG/dhdsp.htm (last accessed 4/2007)
3. Bray MS. Genetic and environmental factors in cardiovascular disease, in Human Genome Epidemiology. Khoury MJ, Little J, Burke W (eds). New York, NY: Oxford University Press 2004:436-450.
4. Hokanson JE, Kamboh MI, Scarboro S, Eckel RH, Hamman RF. Effects of the hepatic lipase gene and physical activity on coronary heart disease risk. Am J Epid 2003;158(9):836-843.