Effects of the Hepatic Lipase Gene and Physical Activity on Coronary Heart Disease Risk

John E. Hokanson1 , M. Ilyas Kamboh2, Sharon Scarboro1, Robert H. Eckel3 and Richard F. Hamman1

1 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO.
2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
3 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO.

Received for publication December 20, 2002; accepted for publication April 28, 2003.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
There are environmental determinants and genetic susceptibility to coronary heart disease (CHD); however, identifying factors that modify genetic risk has been difficult. Evidence suggests that a common polymorphism in the hepatic lipase gene (LIPC-480C>T) may be related to susceptibility to CHD and that physical activity is a behavioral factor associated with CHD. This population-based prospective study in the San Luis Valley of Colorado investigated the role of the LIPC-480C>T polymorphism in predicting clinical CHD and the modifying effect of physical activity. Hispanics and non-Hispanic Whites (n = 966) were followed for 14 years (1984–1998); 91 CHD events occurred. The LIPC-480 TT genotype predicted an increase in CHD in both ethnic groups, and physical activity altered this relation. In the full cohort, the rate of CHD was significantly elevated among subjects with the high-risk genotype and normal levels of physical activity (hazard ratio = 2.58, 95% confidence interval: 1.39, 4.77) but was not elevated among those with the high-risk genotype who participated in vigorous physical activity (hazard ratio = 0.52, 95% confidence interval: 0.12, 2.19) (reference group: LIPC-480 CC/CT, normal physical activity). Thus, in this prospective cohort study, the LIPC-480 TT genotype increased susceptibility to CHD only in those subjects with normal levels of physical activity, not in those with the high-risk genotype who were vigorously active.

cohort studies; coronary disease; genetic predisposition to disease; polymorphism (genetics); risk factors

Abbreviations: Abbreviations: CHD, coronary heart disease; HDL, high density lipoprotein; LDL, low density lipoprotein; SD, standard deviation.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Coronary heart disease (CHD) is the leading cause of death in the industrialized world (1). A number of factors predict CHD; however, a large proportion of events remains unexplained (2). Physical activity has long been recognized as influencing CHD risk, although the mechanisms are not fully understood (3). Increased physical activity leads to greater cardiorespiratory fitness, decreased blood pressure and body weight, and increased high density lipoprotein (HDL) cholesterol, all of which lead to a more favorable CHD risk profile (47). A recent meta-analysis showed a significant protective effect of physical activity on CHD (8). Despite this overall favorable effect, striking variability exists in the physiologic responses to exercise (9).

There are also genetic influences on CHD susceptibility. The greatest successes in identifying susceptibility genes for CHD have generally been confined to relatively rare disorders, for example, familial hypercholesterolemia due to LDL receptor mutations (10). Identifying common CHD susceptibility genes has not been as successful, in part because of the complex nature of CHD risk.

Hepatic lipase is a key rate-limiting enzyme in lipid and lipoprotein metabolism (9, 1114) that is modified by exercise (15, 16). Overall, hepatic lipase activity decreases with exercise; however, there is heterogeneity in this response, with some subjects showing no significant changes in hepatic lipase activity with exercise (17). A common promoter polymorphism in the hepatic lipase gene (LIPC-480C>T) is responsible for differential effects of physical activity on HDL cholesterol levels and modifies the relation between obesity and hepatic lipase (18, 19).

Recent studies have revealed the importance of the LIPC-480C>T polymorphism as a susceptibility marker for increased CHD, despite the relation between the LIPC-480 T allele and higher HDL cholesterol levels. The LIPC-480 T allele is associated with endothelial dysfunction (20), coronary artery calcification (21), the extent of coronary stenosis in patients with CHD (22), and prevalent CHD case-control status in men (23, 24). Given the apparent relation with CHD, the interaction between the LIPC-480C>T polymorphism and physical activity, and the variable response of hepatic lipase to exercise, the current investigation was designed to examine the impact of the LIPC-480C>T polymorphism and physical activity on clinical CHD in a population-based prospective study.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The study population we analyzed consisted of subjects without diabetes or impaired glucose tolerance at baseline from the San Luis Valley Diabetes Study, a population-based prospective cohort study of diabetes and its consequences in a biethnic population of Hispanics and non-Hispanic Whites (25). These study subjects were ascertained by using a geographic two-stage sampling procedure within the two-county area of the San Luis Valley of rural southern Colorado. All residential structures were identified by using maps, directories, aerial photography, and utility customer service records. A 21 percent random sample of occupied structures was selected and its residents contacted to identify all persons living in the household and their demographic characteristics; 96.6 percent of eligible households completed the interview. The second stage of recruitment consisted of a random sample of subjects aged 20–74 years at the baseline visit (1984–1992) who agreed to undergo a fasting, 2-hour, 75-g oral glucose tolerance test (68.4 percent of those eligible). Diabetes status was based on the 1995 World Health Organization criteria or subjects using oral hypoglycemic agents or insulin. All participants completed a clinic examination that included anthropomorphic measures, blood draw for laboratory measures, and diet, physical activity, and medical history questionnaires. Hypertension was defined as current use of antihypertensive medications or a diastolic blood pressure of >=90 mmHg or a systolic blood pressure of >=140 mmHg from the mean blood pressure of the second and third measurements of the fifth-phase tone auscultated from the right arm by using a mercury sphygmomanometer after the subject rested in the supine position for 5 minutes. All procedures were approved by the Colorado Multiple Institutional Review Board, and all subjects provided signed informed consent.

Morbidity and mortality follow-up
Vital status and CHD morbidity were determined subsequent to the baseline visit through 1998 by yearly telephone interviews, obituary monitoring, or death certificate searches of the Colorado State Department of Health. Medical records or autopsy or coroner’s reports were obtained for those for whom events occurred. Cause of death was determined by a three-member committee and was coded by using International Classification of Diseases, Ninth Revision, criteria. CHD included codes 410–414.9 (acute, subacute, and chronic ischemic heart disease). Nonfatal CHD was defined as a reported heart attack or an electrocardiogram major Q-wave abnormality (Minnesota code 1.1–1.2). This rural population is relatively stable, with follow-up status determined for 98 percent of all participants.

Laboratory methods
Plasma was collected after a 12-hour fast. Total cholesterol, HDL cholesterol, and triglycerides were determined by enzymatic methods, and LDL cholesterol was determined by the Friedewald equation if triglyceride levels were less than 400 mg/dl. LIPC-480 genotypes were determined by digestion of the polymerase chain reaction–amplified promoter sequences with NlaIII (26). Nomenclature of the LIPC promoter polymorphism (i.e., LIPC-480) is based on the sequence published by Cai et al. (27) and represents the same position as the LIPC-514 polymorphism.

Physical activity assessment
Study subjects were interviewed in English or Spanish regarding participation in vigorous activity at both work and during leisure time (refer to Mayer-Davis et al. (28) for details). Vigorous activity included any activity that the study participant considered strenuous or caused fatigue, increased heart rate, or sweating. Study subjects were ranked on the basis of the frequency and duration of vigorous activity as participating in no vigorous physical activity (sedentary), vigorous activity less than three times a week for at least 20 minutes (moderate), or vigorous activity three or more times a week for at least 20 minutes (vigorous). Analyses indicated that sedentary and moderate physical activity had similar relations with CHD; therefore, these two categories were combined in subsequent analyses.

Statistical methods
Analysis of variance was used for simple comparisons (Wilcoxon’s or Kruskal-Wallis rank tests if the data were not normally distributed). In this paper, results are presented as mean (standard deviation (SD)). Differences in lipids by LIPC-480 genotype were adjusted for age, sex, and ethnicity. To compare genotype distributions, we used the {chi}2 test and Mantel-Haenszel stratified analysis (stratified by ethnicity).

Cox proportional hazards modeling was used to test the a priori hypothesis of a relation between the LIPC-480C>T polymorphism and CHD events (age to CHD, fatal or nonfatal, as the dependent variable) and an interaction with physical activity after accounting for other potential predictive variables. To date, no other candidate genes have been examined as predictors of CHD in this cohort. Interactions with the LIPC-480 genotype were included based on potential physiologic relevance (i.e., physical activity, hypertension, diabetes) as well as ethnicity, with a significance level of p = 0.10 to be included in the model. The strength of the association was expressed as a hazard ratio. A backwards stepwise method was used to determine independent predictive variables. Analyses were performed by using the Statistical Analysis System (SAS, version 8.1; SAS Institute, Inc., Cary, North Carolina).

Variables that did not remain in the final model included smoking, LDL cholesterol, triglyceride (log transformed), waist circumference, body mass index, and lipid-lowering medications (gemfibrozil, n = 7; cholestryramine, n = 3; and lovastatin, n = 5). Smoking was analyzed as yes/no and as current/ex/never smokers. Although there was an increase in the proportions of cases among the ex-smokers and current smokers (8 percent among never smokers, 13 percent among ex-smokers, and 9 percent among current smokers), these differences were not statistically significant. This finding is consistent with early reports from this cohort (29, 30). LDL cholesterol did not remain in the model that included total cholesterol. When total cholesterol was removed from the model, LDL cholesterol was a significant predictor of CHD (p < 0.01). Triglyceride is an independent predictor of CHD in some, but not all, cohorts (31), and it may be complicated by a nonlinear relation between triglyceride and CHD (32).

The role of ethnicity in the relation between the LIPC-480 polymorphism and CHD was considered in the following ways. First, the proportion of CHD cases with each genotype was not different between ethnic groups (figure 1). Second, Kaplan-Meier survival curves were stratified by ethnicity, and LIPC-480 genotypes showed a similar CHD-free survival in both Hispanics and non-Hispanic Whites. Third, ethnicity was forced to remain as a confounding variable in the Cox proportional hazards model, and the effect of the LIPC-480 genotype on CHD was independent of ethnicity. Fourth, an interaction between ethnicity and the LIPC-480 genotype was tested; this interaction term was not significant (p = 0.97) and did not alter the relation between LIPC-480 genotype and CHD. Finally, multivariate analyses were also performed for Hispanics and non-Hispanic Whites separately, and the risk estimates for the association of LIPC-480 TT genotype with CHD were of similar magnitude (Hispanics—hazard ratio = 2.39, 95 percent confidence interval: 1.14, 5.03; non-Hispanic Whites—hazard ratio = 2.98, 95 percent confidence interval: 0.89, 9.96).



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FIGURE 1. Percentage of subjects with coronary heart disease (CHD) within each LIPC-480 genotype, by ethnic group, San Luis Valley, Colorado, 1984–1998. Solid bars, Hispanics (n = 397); open bars, non-Hispanic Whites (n = 569). * When compared with LIPC-480 CC/CT subjects, LIPC-480 TT subjects included a significantly higher proportion with CHD (p < 0.05, by Mantel-Haentzel {chi}2 test, stratified by ethnicity). LIPC, hepatic lipase gene.

 

    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The study population (n = 966) consisted of 397 Hispanics and 569 non-Hispanic Whites (table 1). Age at the baseline visit (1984–1992) was 51.0 (SD, 12.6) years for Hispanics and 52.4 (SD, 11.3) years for non-Hispanic Whites. For Hispanics compared with non-Hispanic Whites, triglyceride levels were significantly higher (148 (SD, 69.6) mg/dl vs. 142 (SD, 95.2) mg/dl, p = 0.02), and HDL cholesterol levels were marginally lower (49 (SD, 14) mg/dl vs. 51 (SD, 14) mg/dl, p = 0.08). Other lipids, blood pressure, and body mass index were not different between the ethnic groups. Waist-to-hip ratio was significantly greater in Hispanics compared with non-Hispanic Whites (0.94 (SD, 0.08) vs. 0.93 (SD, 0.08), p = 0.002). The hepatic lipase gene promoter polymorphism was significantly more common in Hispanic than in non-Hispanic White subjects (LIPC-480 T allele frequency, 0.47 (SD, 0.02) vs. 0.19 (SD, 0.01); p < 0.001). Genotype distributions did not deviate from Hardy-Weinberg proportions in either ethnic group.


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TABLE 1. Baseline characteristics* (1984–1992) of study participants from the San Luis Valley, Colorado, separated by ethnicity{dagger}
 
The cohort was followed for 14 years, and 91 CHD events were recorded. Those for whom CHD events occurred were older (59.3 (SD, 9.4) years vs. 51.1 (SD, 11.9) years, p < 0.001) and more likely to be male (76.9 percent vs. 45.7 percent, p < 0.001) (table 2). Those with CHD had a worse lipid profile, with significantly higher triglyceride, total and LDL cholesterol, and lower HDL cholesterol levels. Body mass index, waist-to-hip ratio, and blood pressure all were significantly higher in those who had CHD events. No difference in ethnicity was found between those with or without CHD. There was a significant difference in the LIPC-480 genotype distribution between CHD cases and those without CHD, with an excess of LIPC-480 TT homozygous subjects among those with CHD compared with those without CHD (p = 0.04).


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TABLE 2. Baseline characteristics* (1984–1992) of study participants from the San Luis Valley, Colorado, separated by CHD{dagger} events{ddagger}
 
No significant differences were found in HDL cholesterol (p = 0.32), HDL2 cholesterol (p = 0.55), or HDL3 cholesterol (p = 0.17) by LIPC-480 genotype. We found a modest difference in plasma triglyceride levels between LIPC-480 genotypes (152 (SD, 73.0) mg/dl, 151 (SD, 107.0) mg/dl, and 138 (SD, 74.9) mg/dl for LIPC-480 TT, CT, and CC genotypes, respectively; p = 0.03).

Kaplan-Meier survival curves showed that subjects homozygous for the LIPC-480 TT genotype had a worse CHD-free survival compared with subjects with the LIPC-480 CC or CT genotype (p = 0.01) (figure 2). Overall cumulative survival for LIPC-480 TT subjects was 54 percent compared with 76 percent and 80 percent for LIPC-480 CT and CC subjects, respectively. The CHD-free survival was not different between LIPC-480 CC and LIPC-480 CT subjects (p = 0.31); therefore, these two groups were combined for further analysis.



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FIGURE 2. Kaplan-Meier survival curves according to LIPC-480 genotype, San Luis Valley, Colorado, 1984–1998. Coronary heart disease (CHD) survival function represents the proportion of subjects free of CHD based on age at first event over a median of 13.5 years of follow-up. LIPC, hepatic lipase gene.

 
Cox proportional hazards analysis indicated that the LIPC-480 TT genotype predicted CHD events. When an interaction between LIPC-480 genotype and physical activity was modeled, levels of physical activity modulated the relation between LIPC-480 genotype and CHD (table 3). To further investigate the relation among LIPC-480 genotype, physical activity, and CHD, subjects were categorized into four groups based on genotype (LIPC-480 TT vs. CC/CT) and vigorous physical activity versus sedentary or moderate physical activity. Estimates indicated a significant increase in risk of CHD for LIPC-480 TT subjects who did not participate in vigorous physical activity (p = 0.003) (table 3, figure 3). Vigorous physical activity did not significantly alter the risk of CHD for subjects with the LIPC-480 CC or CT genotype (p = 0.62); however, a reduced risk due to vigorous physical activity was found for subjects with the LIPC-480 TT genotype (p = 0.03 comparing vigorous physical activity with sedentary or moderate physical activity among LIPC-480 TT subjects). Subjects with this high-risk genotype who participated in vigorous physical activity did not have an increase in CHD (hazard ratio = 0.52, 95 percent confidence interval: 0.12, 2.19), while those with the high-risk genotype who did not participate in vigorous physical activity did have a significant increase in CHD (hazard ratio = 2.58, 95 percent confidence interval: 1.39, 4.77) (reference group for both comparisons: LIPC-480 CC/CT without vigorous activity).


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TABLE 3. Cox proportional hazard ratios predicting coronary heart disease events for the follow-up period of 1984–1998, San Luis Valley, Colorado
 


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FIGURE 3. Hazard ratios for coronary heart disease events according to LIPC-480 genotype and levels of physical activity, San Luis Valley, Colorado, 1984–1998. Diamonds, point estimates; error bars, 95% confidence intervals. The confidence interval that does not include 1.0 is statistically significant compared with the reference category (LIPC-480 CC/CT, sedentary/moderate physical activity, n = 525) at the p < 0.05 level. Hazard ratios and confidence intervals are plotted on a natural logarithmic scale. LIPC-480 TT, sedentary/moderate physical activity (n = 61); LIPC-480 CC/CT, vigorous physical activity (n = 328); LIPC–480 TT, vigorous physical activity (n = 46). LIPC, hepatic lipase gene.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study showed that the LIPC-480 TT genotype predicted an increase in CHD for subjects who participated in normal levels of physical activity, but this increase was not found for subjects with the high-risk genotype who took part in vigorous physical activity. Those subjects who carried the LIPC-480 TT genotype and participated in activities they considered strenuous—those that caused fatigue, increased heart rate, or sweating for 20 minutes three times a week—did not appear to have the increase in CHD associated with this high-risk genotype.

The mechanism by which the LIPC-480C>T polymorphism promotes CHD has yet to be elucidated. In this study, the effect of the LIPC-480 TT genotype on CHD was independent of HDL cholesterol. Others have shown a modest increase in HDL cholesterol associated with the LIPC-480 T allele (23, 33, 34), which was not observed in the current study. One potential mechanism may relate to the role that hepatic lipase plays in remnant lipoprotein metabolism (35, 36). Variations in the hepatic lipase gene are associated with higher levels of intermediate density lipoprotein (14), the lipid content of intermediate density lipoprotein (37), and higher LpCIII:B particles (34). These atherogenic lipoproteins (38, 39) were not measured in the current study and may account for the observed relation between the LIPC-480 polymorphism and CHD.

Accumulating evidence now seems to support a role for the LIPC-480 T allele and increased susceptibility to CHD. The LIPC-480 T allele is also associated with a decrease in coronary flow reserve (20), the presence (21) and extent (21, 22) of subclinical CHD, and prevalent case-control status in some (23, 24), but not all (37, 40), studies. To our knowledge, no studies have reported a protective effect of the LIPC-480 T allele despite its impact on HDL cholesterol levels, and no studies have investigated an interaction between LIPC-480 genotypes and physical activity on risk of CHD.

It was intriguing to note the effect of physical activity for subjects with the LIPC-480 TT genotype that has been associated with decreased coronary flow reserve (20), a measure of endothelial dysfunction. Exercise has a favorable effect on coronary flow reserve (41), perhaps by decreasing tri-glyceride-rich remnant lipoproteins that alter endothelial function (42). The effect of vigorous physical activity on the risk of CHD associated with the LIPC-480C>T polymorphism may be due to the exercise-induced decrease in remnant lipoproteins and a subsequent increase in coronary flow reserve in subjects with a genetic susceptibility to these abnormalities. Confirmation of this hypothesis will require further study.

Of particular importance is that the impact of the high-risk genotype appears to be altered by levels of physical activity. This interaction of gene and environment draws particular attention to the need to investigate the efficacy of targeted intervention studies that lead to increases in physical activity. Vigorous activity of 20 minutes or more three or more times a week limits the adverse effect of the LIPC-480 high-risk genotype on CHD. In this study, physical activity was assessed by using a structured interview. This method has been validated against other measures of physical activity; however, there undoubtedly is misclassification in this measure. It is most likely that this misclassification is nondifferential with respect to both LIPC-480 genotype and subsequent CHD; thus, it is expected that the true impact of vigorous physical activity may be greater than observed in this study. Given that the LIPC-480C>T polymorphism is relatively common (allele frequency of 0.19 in non-Hispanic Whites, 0.47 in Hispanics, and 0.45–0.54 in African-Americans (33, 43)) stresses the potential benefit of a successful physical activity intervention targeted at subjects who carry the high-risk genotype. In fact, one would anticipate an even greater impact of increased physical activity mediated through mechanisms other than the hepatic lipase gene, such as weight loss and cardiorespiratory fitness. The benefits of changing physical activity levels in this high-risk group remains to be determined, however.

In conclusion, in this population-based prospective study, the hepatic lipase promoter polymorphism (LIPC-480 TT genotype) predicted a greater than twofold increase in CHD. The increase in CHD associated with this high-risk genotype was seen only for subjects who participated in normal levels of physical activity. Subjects who carried the high-risk genotype and who participated in vigorous physical activity (20 minutes three times a week) did not exhibit an increase in CHD. These data support a role for gene-environment interaction in the susceptibility to coronary disease and may provide an important impetus for increasing levels of physical activity to prevent CHD in high-risk populations.


    ACKNOWLEDGMENTS
 
These studies were supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant DK30747-16 (R. F. Hamman, Principal Investigator) and National Institutes of Health/National Heart, Lung, and Blood Institute grant RO1-HL4672 (M. I. Kamboh, Principal Investigator). Lipid measurements were performed at the Adult Clinical Research Center Core Laboratory at the University of Colorado Health Sciences Center, funded by grant M01 RR0051 (R. H. Eckel, Director).


    NOTES
 
Correspondence to Dr. John E. Hokanson, Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B119, Denver, CO 80262 (e-mail: john.hokanson{at}UCHSC.edu). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. American Heart Association. Heart and stroke facts, 1998. Dallas, TX: American Heart Association, 1998.
  2. Hoeg JM. Evaluating coronary heart disease risk. Tiles in the mosaic. JAMA 1997;277:1387–90.[CrossRef][ISI][Medline]
  3. Despres JP, Lamarche B. Low-intensity endurance exercise training, plasma lipoproteins and the risk of coronary heart disease. J Intern Med 1994;236:7–22.[ISI][Medline]
  4. Gordon DJ, Witztum JL, Hunninghake D, et al. Habitual physical activity and high-density lipoprotein cholesterol in men with primary hypercholesterolemia. The Lipid Research Clinics Coronary Primary Prevention Trial. Circulation 1983;67:512–20.[Abstract]
  5. Paffenbarger RS Jr, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol 1995;142:889–903.[ISI][Medline]
  6. Peters RK, Cady LD Jr, Bischoff DP, et al. Physical fitness and subsequent myocardial infarction in healthy workers. JAMA 1983;249:3052–6.[Abstract]
  7. Salonen JT, Slater JS, Tuomilehto J, et al. Leisure time and occupational physical activity: risk of death from ischemic heart disease. Am J Epidemiol 1988;127:87–94.[Abstract]
  8. Williams PT. Physical fitness and activity as separate heart disease risk factors: a meta-analysis. Med Sci Sports Exerc 2001;33:754–61.[ISI][Medline]
  9. Couillard C, Despres JP, Lamarche B, et al. Effects of endurance exercise training on plasma HDL cholesterol levels depend on levels of triglycerides: evidence from men of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Arterioscler Thromb Vasc Biol 2001;21:1226–32.[Abstract/Free Full Text]
  10. Goldstein JL, Hobbs HH, Brown MS. Familial hyper-cholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The metabolic basis of inherited diseases. New York, NY: McGraw-Hill, 1995:1981–2030.
  11. Auwerx JH, Marzetta CA, Hokanson JE, et al. Large buoyant LDL-like particles in hepatic lipase deficiency. Arteriosclerosis 1989;9:319–25.[Abstract]
  12. Kuusi T, Saarinen P, Nikkila EA. Evidence for the role of hepatic endothelial lipase in the metabolism of plasma high density lipoprotein2 in man. Atherosclerosis 1980;36:589–93.[ISI][Medline]
  13. Zambon A, Austin MA, Brown BG, et al. Effect of hepatic lipase on LDL in normal men and those with coronary artery disease. Arterioscler Thromb 1993;13:147–53.[Abstract]
  14. Zambon A, Deeb SS, Bensadoun A, et al. In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity. J Lipid Res 2000;41:2094–9.[Abstract/Free Full Text]
  15. Giada F, Baldo-Enzi G, Baiocchi MR, et al. Specialized physical training programs: effects on serum lipoprotein cholesterol, apoproteins A-I and B and lipolytic enzyme activities. J Sports Med Phys Fitness 1991;31:196–203.[ISI][Medline]
  16. Mendoza SG, Carrasco H, Zerpa A, et al. Effect of physical training on lipids, lipoproteins, apolipoproteins, lipases, and endogenous sex hormones in men with premature myocardial infarction. Metabolism 1991;40:368–77.[ISI][Medline]
  17. Leon AS, Gaskill SE, Rice T, et al. Variability in the response of HDL cholesterol to exercise training in the HERITAGE Family Study. Int J Sports Med 2002;23:1–9.[CrossRef][ISI][Medline]
  18. Carr MC, Hokanson JE, Deeb SS, et al. A hepatic lipase gene promoter polymorphism attenuates the increase in hepatic lipase activity with increasing intra-abdominal fat in women. Arterioscler Thromb Vasc Biol 1999;19:2701–7.[Abstract/Free Full Text]
  19. Hokanson JE, Hamman RF, Eckel RH, et al. Gene-environment interaction in the regulation of HDL: the hepatic lipase promoter polymorphism modulates the physical activity associated increase in HDL. (Abstract). Circulation 2001;103:P08.
  20. Fan Y, Laaksonen R, Janatuinen T, et al. Hepatic lipase gene variation is related to coronary reactivity in healthy young men. Eur J Clin Invest 2001;31:574–80.[CrossRef][ISI][Medline]
  21. Hokanson JE, Cheng S, Snell-Bergeon JK, et al. A common polymorphism in the hepatic lipase gene (LIPC-480 C>T) is associated with an increase in coronary artery calcification in type 1 diabetes. Diabetes 2002;51:1208–13.[Abstract/Free Full Text]
  22. Dugi KA, Brandauer K, Schmidt N, et al. Low hepatic lipase activity is a novel risk factor for coronary artery disease. Circulation 2001;104:3057–62.[Abstract/Free Full Text]
  23. Jansen H, Verhoeven AJ, Weeks L, et al. Common C-to-T substitution at position-480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients. Arterioscler Thromb Vasc Biol 1997;17:2837–42.[Abstract/Free Full Text]
  24. Ji J, Herbison CE, Mamotte CD, et al. Hepatic lipase gene-514 C/T polymorphism and premature coronary heart disease. J Cardiovasc Risk 2002;9:105–13.[CrossRef][ISI][Medline]
  25. Hamman RF, Marshall JA, Baxter J, et al. Methods and prevalence of non-insulin-dependent diabetes mellitus in a biethnic Colorado population. The San Luis Valley Diabetes Study. Am J Epidemiol 1989;129:295–311.[Abstract]
  26. Guerra R, Wang J, Grundy SM, et al. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol. Proc Natl Acad Sci U S A 1997;94:4532–7.[Abstract/Free Full Text]
  27. Cai SJ, Wong DM, Chen SH, et al. Structure of the human hepatic triglyceride lipase gene. Biochemistry 1989;28:8966–71.[ISI][Medline]
  28. Mayer EJ, Alderman BW, Regensteiner JG, et al. Physical-activity-assessment measures compared in a biethnic rural population: the San Luis Valley Diabetes Study. Am J Clin Nutr 1991;53:812–20.[Abstract]
  29. Rewers M, Shetterly SM, Hoag S, et al. Is the risk of coronary heart disease lower in Hispanics than in non-Hispanic whites? The San Luis Valley Diabetes Study. Ethn Dis 1993;3:44–54.[Medline]
  30. Rewers M, Shetterly SM, Baxter J, et al. Prevalence of coronary heart disease in subjects with normal and impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a biethnic Colorado population. The San Luis Valley Diabetes Study. Am J Epidemiol 1992;135:1321–30.[Abstract]
  31. Hokanson JE, Austin MA. Plasma triglyceride is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3:213–19.[Medline]
  32. Hokanson JE. Hypertriglyceridemia and risk of coronary heart disease. Curr Cardiol Rep 2002;4:488–93.[Medline]
  33. Zambon A, Deeb SS, Hokanson JE, et al. Common variants in the promoter of the hepatic lipase gene are associated with lower levels of hepatic lipase activity, buoyant LDL, and higher HDL2 cholesterol. Arterioscler Thromb Vasc Biol 1998;18:1723–9.[Abstract/Free Full Text]
  34. Jansen H, Chu G, Ehnholm C, et al. The T allele of the hepatic lipase promoter variant C-480T is associated with increased fasting lipids and HDL and increased preprandial and postprandial LpCIII:B: European Atherosclerosis Research Study (EARS) II. Arterioscler Thromb Vasc Biol 1999;19:303–8.[Abstract/Free Full Text]
  35. Santamarina-Fojo S, Haudenschild C, Amar M. The role of hepatic lipase in lipoprotein metabolism and atherosclerosis. Curr Opin Lipidol 1998;9:211–19.[CrossRef][ISI][Medline]
  36. Huff MW, Miller DB, Wolfe BM, et al. Uptake of hypertriglyceridemic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans. J Lipid Res 1997;38:1318–33.[Abstract]
  37. Tahvanainen E, Syvanne M, Frick MH, et al. Association of variation in hepatic lipase activity with promoter variation in the hepatic lipase gene. The LOCAT Study Investigators. J Clin Invest 1998;101:956–60.[Abstract/Free Full Text]
  38. Krauss RM, Lindgren FT, Williams PT, et al. Intermediate-density lipoproteins and progression of coronary artery disease in hypercholesterolaemic men. Lancet 1987;2:62–6.[ISI][Medline]
  39. Steiner G, Schwartz L, Shumak S, et al. The association of increased levels of intermediate-density lipoproteins with smoking and with coronary artery disease. Circulation 1987;75:124–30.[Abstract]
  40. Shohet RV, Vega GL, Anwar A, et al. Hepatic lipase (LIPC) promoter polymorphism in men with coronary artery disease. Allele frequency and effects on hepatic lipase activity and plasma HDL-C concentrations. Arterioscler Thromb Vasc Biol 1999;19:1975–8.[Abstract/Free Full Text]
  41. Czernin J, Sun K, Brunken R, et al. Effect of acute and long-term smoking on myocardial blood flow and flow reserve. Circulation 1995;91:2891–7.[Abstract/Free Full Text]
  42. Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol 1997;79:350–4.[CrossRef][ISI][Medline]
  43. Nie L, Wang J, Clark LT, et al. Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence postheparin plasma hepatic lipase activity. J Lipid Res 1998;39:1127–30.[Abstract/Free Full Text]