© 1997 American Heart Association, Inc.
Articles |
Familial Resemblance of Plasma Lipids, Lipoproteins and Postheparin Lipoprotein and Hepatic Lipases in the HERITAGE Family Study
From the Division of Kinesiology, Laval University Medical School, Québec, Canada (L.P., J.P.D., J.G., C.B.); the Division of Biostatistics, Washington University Medical School, St. Louis, MO (T.R., D.C.R.); the Lipid Research Clinic Center, Laval University Hospital Center, Québec, Canada (J.P.D., J.B.); the School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, MN (A.S.L.); the Departments of Genetics and Psychiatry, Washington University Medical School, St. Louis, MO (D.C.R.); the Department of Kinesiology, Indiana University, Bloomington, IN (J.S.S.); and the Department of Kinesiology and Health Education, The University of Texas, Austin, TX (J.H.W.).
Correspondence to Louis Pérusse, PhD, Physical Activity Sciences Laboratory, Laval University, Québec G1K 7P4, Canada. E-mail louis.perusse{at}kin.msp.ulaval.ed
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract The familial aggregation of lipids and lipoproteins and plasma postheparin triglyceride lipases was investigated in 86 Caucasian families participating in the HERITAGE Family study, a study investigating the role of genetic factors in the adaptation to exercise training and its relationships with cardiovascular disease risk factors. Accordingly, sedentary subjects were recruited, tested for a battery of measurements, exercise trained for 20 weeks, and were re-measured. The present report includes plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides, and postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities measured in 437 sedentary individuals (171 parents and 266 adult offspring) before training. Significant familial resemblance was observed for all the age-adjusted phenotypes. The pattern of familial correlations reveals no spouse correlations but significant parent-offspring and sibling correlations for total cholesterol, HDL-cholesterol and LDL-cholesterol with heritability (h2) estimates of 62%, 83%, and 50%, respectively. For plasma triglyceride concentrations (h2=55%) and HL activity (h2=40%), significant spouse correlations were found in addition to parent-offspring and sibling correlations, suggesting that common familial environment in addition to genetic factors contribute to the familial resemblance. For plasma LPL activity, there was no spouse correlation, but sex differences were found in the familial correlations with higher heritabilities in female pairs (h2=76%) compared to male pairs (h2=30%) and opposite-sex pairs (h2=44%). These results confirm the findings of previous family studies showing that genetic factors are major determinants of the familial resemblance in plasma lipids and lipoproteins and suggest the presence of sex differences in the heritability of postheparin LPL activity.
Key Words: lipoproteins • lipids • cholesterol • lipases • coronary heart disease
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Coronary heart disease (CHD) continues to be a major cause of morbidity and premature mortality in Western countries. Among risk factors of CHD, dyslipidemic states have been recognized to be important correlates and predictors of the disease. There is extensive epidemiological evidence showing that a dyslipidemic profile, characterized by high plasma levels of total cholesterol, triglycerides and LDL and reduced concentrations of HDL, is strongly associated with an increased risk of CHD.1–5 There is also evidence from clinical trials that reduction of plasma cholesterol and LDL-cholesterol levels and increase in HDL-cholesterol concentrations contribute to reduce the risk of CHD,6–7 even in patients who do not exhibit marked elevation of plasma cholesterol levels.8
Because of their key role in the development of atherosclerosis and CHD, the study of genetic factors in modulating plasma lipid and lipoprotein levels has important clinical implications. Studies have clearly established that genetic factors contribute significantly to interindividual differences in blood lipids and lipoproteins in normolipemic individuals with heritability estimates accounting for about 25% to 80% of the phenotypic variance depending on the phenotype considered.9–14 In most studies, the genetic effect was more important than environmental effects shared among family members.
LPL and HL are enzymes involved in the hydrolysis of triglyceride-rich lipoproteins and play an important role in the metabolism of lipoproteins and in the regulation of circulating levels of HDL-cholesterol. The LPL is responsible for the delipidation of chylomicrons and very low density lipoproteins and a higher LPL activity in the plasma has been associated with reduced plasma triglyceride levels as well as with an increased HDL-cholesterol levels, particularly for the HDL2 subfraction.15,16 In contrast, HL is involved in reverse cholesterol transport and its activity is negatively correlated with plasma HDL-cholesterol levels.17,18 The evidence for a role of genetic factors in these two lipolytic enzymes has been mainly derived from molecular studies. Thus, mutations in the genes coding for these enzymes have been shown to result in severe forms of dyslipoproteinemia19,20 and some studies reported associations between polymorphisms in the LPL gene and levels of lipids and lipoproteins.21–23 Data from one twin study24 based on 17 MZ and 18 DZ male twin pairs reported no significant genetic effect for LPL, in contrast to HL that exhibited a high pairwise correlation in MZ twins (r=0.80), but not in DZ twins (r=0.21).
In the present study, the familial factors underlying the variation in lipoproteins and postheparin LPL and HL activities in the HERITAGE Family Study are investigated using a familial correlation model. Genetic and environmental inferences made by an inspection of familial correlations among spouses, siblings and between parents and offspring suggests that genetic factors significantly contribute to the familial aggregation of lipoproteins and postheparin lipase activities with heritability estimates ranging from about 40% to 80% of the age-adjusted phenotypic variance.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sample
Subjects of the HERITAGE Family Study were used for the purpose of this study. The HERITAGE study is a multicenter study designed to investigate the effects of regular exercise on several cardiovascular disease and diabetes risk factors and to determine the role of genetic factors in cardiovascular, metabolic, and hormonal responses to endurance exercise training. The specific aims, design, and measurements of the study have been described in detail elswhere.25 Briefly, Caucasian and Black families are recruited, tested, exercise-trained in four clinical centers with a rigorously controlled standardized training program for 20 weeks and re-tested. Only baseline (before training) data in Caucasian families are reported and analyzed in the present study.
Recruitment of families was based on extensive publicity and advertisement. The following exclusion criteria were used to screen subjects for recruitment. The primary requirement was that the families were sedentary, defined at baseline as no regular physical activity over the previous 6 months. Families with some nonsedentary members were included provided that the nonsedentary individual(s) detrained for at least 6 months. Second, individuals were required to be between the ages of 16 years to 65 years (16 years to 40 years for children, and 65 years or less for parents) in order to avoid maturation (low end) and aging (high end) complications. Third, individuals had to be in good health in order to complete the maximal exercise training. Fourth, individuals with a BMI greater than 40 kg/m2 were usually excluded because of potential metabolic abnormalities and exercise difficulties associated with extreme obesity. Fifth, individuals with blood pressures greater than 159 mm Hg for systolic and 99 mm Hg for diastolic were also excluded. Finally, individuals with any life-threatening condition or disease that could be aggravated by cycle exercise were excluded. More details on exclusion criteria can be found elsewhere.25 In the current study, data on a total of 437 individuals belonging to 86 Caucasian families were available.
Measures
Fasting blood samples were drawn at each Clinical Center and
prepared according to a standard protocol. For women, samples were
obtained in the early follicular phase. Samples were then sent to the
lipid core laboratory at the Lipid Research Center of the Laval
University Medical Center for determinations of plasma lipids,
lipoproteins and postheparin lipolytic activities.
Cholesterol levels in whole plasma and in lipoprotein
fractions and plasma triglyceride levels were measured by
enzymatic methods using the Technicon RA-1000 analyzer. Plasma
VLDL were isolated by
ultracentrifugation26 and the HDL
fraction was obtained after precipitation of LDL in the infranatant
with heparin and MnCl2.27
Plasma LPL and HL activities were also measured in the subjects after a
12-hour overnight fast and 10 minutes after intravenous
injection of heparin (60 IU/kg body weight). The postheparin lipase
activities were measured using a modification of the method of
Nilsson-Ehle and Ekman28 as previously
described.29 The two lipolytic enzyme activities
were expressed as nmoles of oleic acid released per ml of plasma
per min.
Because of the multicenter nature of the HERITAGE study, extensive quality assurance and quality control measures were implemented to ensure that data were of the highest quality.30 The reproducibility of lipids, lipoproteins, and postheparin lipase assays was determined using an intracenter quality control study30 by generating split samples from 60 nonHERITAGE subjects (15 in each of the clinical center) that were assayed in a blind fashion by the lipid core laboratory. The reproducibility of repeated assays based on split samples was found to be very high, with intraclass correlation coefficients over 0.95. Coefficients of variation for repeated assays ranged from about 1% to 5% for the variables of the present study.
Age Adjustments
Before any data adjustments, triglyceride values
were log transformed. Each measure was then adjusted for the effects of
age using a stepwise multiple regression procedure, separately in each
of the 4 sex by generation groups. In summary, a given measure was
regressed on a polynomial in age in a stepwise manner, retaining only
those terms that were significant at the 5% level. The
phenotype used in the genetic analysis was defined as
the age-adjusted and standardized residual score from the regression
analysis. The percentages of variance accounted for by age in
each of the sex by generation groups ranged from 3% to 24% for total
cholesterol, 1% to 2% for HDL-cholesterol,
2% to 21% for LDL-cholesterol, 2% to 10% for HL, and
2% to 9% for LPL. For triglycerides, significant age
effects were found only in sons and accounted for 15% of the
variance.
Familial Correlation Model
The model was based on 4 groups of individuals [fathers
(f), mothers (m), sons (s), and
daughters (d)], giving rise to 8 interindividual
correlations in 3 familial classes [1 spouse (fm), 4
parent-offspring (fs, fd, ms,
md), and 3 sibling (ss, dd,
sd)]. The maximum likelihood computer program
SEGPATH31 fitted the model directly to the family
data under the assumption that the phenotypes within a family
jointly follow a multivariate normal distribution. Null
hypotheses were tested using the likelihood ratio test, which is the
difference in minus twice the log-likelihoods (-2 ln L) obtained under
the two different nested models. The likelihood ratio is approximately
distributed as a 
,2 with the degrees of
freedom being the difference in the number of parameters
estimated in the two competing hypotheses. In addition to the
likelihood ratio test, Akaike's32 Information
Criterion (AIC), which is -2 ln L plus twice the number of estimated
parameters, was used to judge the fit of nonnested models.
The "best" model by AIC is the one with the smallest value.
The general model (model 1) and several reduced models (models 2 to 12)
testing specific null hypotheses were fitted to the data. A detailed
description of each of these models is given in the appendix
along with
the parameter constraints involved in each reduced model
and the resulting degrees of freedom. Briefly, two broad classes of
reduced models were considered. First, null hypotheses on sex and
generation differences in the familial correlations included no sex
differences in the offspring (model 2), no sex differences in parents
or offspring (model 3), and no sex nor generation differences (model
4). Other sex-specific models involved same versus opposite sex
correlations with (model 5) and without (model 6) constraint on the
spouse correlation and male versus female versus opposite-sex
correlations with (model 7) and without (model 8) constraint in the
spouse correlation. The spouse correlation is therefore allowed to vary
in models 6 and 8, while it is not in models 5 and 7. Second, null
hypotheses testing the strength of the familial resemblance were also
conducted by familial class, including no spouse resemblance (model 9),
no parent-offspring resemblance (model 10), no sibling resemblance
(model 11), and no familial resemblance at all (model 12). Each null
hypothesis was tested by a likelihood ratio comparison to the general
model. The most parsimonious model was derived by combining all
nonrejected null hypotheses. The AIC was used to select the "best"
sex hypothesis from among the nonnested sex models. Also, when the AIC
for the parsimonious model was larger than that for a null hypothesis,
then the hypothesis with the smallest P-value was added back into the
model until an acceptable fit was obtained.
|
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Table 1
shows the sample sizes,
means, and standard deviations for age and for each of the lipid and
lipase measures, separately in each of the sex and generation groups
(fathers, mothers, sons, and daughters). Based on a comparison of
standard errors, sex differences generally are in the direction of
higher mean levels in males and generation differences are reflected in
higher concentrations in parents. The exceptions involve total
cholesterol (no sex differences),
HDL-cholesterol (higher means in females than in males, and
no generation difference between fathers and sons), and
LDL-cholesterol (no sex difference).
|
The model-fitting results are given in Table 2 for plasma lipid and lipoprotein levels
and in Table 3 for HL and LPL activities.
The results for lipids and lipoproteins (Table 2) indicate the presence
of significant familial aggregation for all lipid variables (model
12 rejected for all variables) with significant
(P<.001) parent-offspring and sibling correlations. Except
for triglycerides, the hypothesis of no spouse resemblance
(model 9) could not be rejected, suggesting that genetic factors are
probably more important than familial environment in determining
interindividual differences in lipids and lipoproteins. Except for
HDL-cholesterol, all the hypotheses involving sex and
generation differences in the familial correlations could not
be rejected (.20
P.97). For HDL-cholesterol,
the models 5 and 7, where the spouse correlation is included and
equated to the opposite-sex familial correlations, were rejected. Based
on the AIC value, the best sex differences hypothesis was model 4 for
cholesterol (AIC=5.51), LDL-cholesterol
(AIC=7.82) and triglycerides (AIC=7.40) and model 3 for
HDL-cholesterol (AIC=7.34). The most parsimonious models
were therefore the combination of models 4 and 9 for total
cholesterol (AIC=5.27) and LDL-cholesterol
(AIC=6.41), combination of models 3 and 9 for
HDL-cholesterol (AIC=6.39) and model 4 for
triglycerides.
|
|
Results for HL and LPL are presented in Table 3
. As for lipids
and lipoproteins, familial resemblance was noted with significant
parent-offspring and sibling correlations (P<.001) and
nonsignificant (P>.05) spouse correlations. For hepatic
lipase, all of the hypotheses testing for no sex differences fit the
data, although those that equate the spouse correlation with the other
familial opposite-sex correlations (models 5 and 7) fit less well.
Among the sex difference hypotheses, model 4 gave the best fit with an
AIC=6.98. Although the parsimonious hypothesis derived by combining
models 4 (no sex nor generation differences) and 9 (no spouse
correlation) were found to fit the data by likelihood ratio
(P=.485), the AIC for this combined model (8.48, results not
shown) was larger than that for model 4 alone (AIC=6.98) which allows
for an additional spouse correlation. Therefore, the most parsimonious
model chosen for hepatic lipase was model 4 involving two correlations,
one between spouses and one for the combined parent-offspring and
sibling resemblance.
For lipoprotein lipase, none of hypotheses testing for no sex differences in the correlations were rejected, and the best one by AIC (10.37) was model 8 allowing for male-male, female-female, and opposite-sex correlations without any restriction the spouse correlation. Therefore, the most parsimonious model was the combination of models 8 and 9 (AIC=8.74), which allows for male-male, female-female, and opposite-sex familial correlations and no spouse resemblance.
Maximum likelihood parameter estimates (correlations
± standard errors) under both the general and the most parsimonious
models are given in Table 4. The familial
correlations for these lipid and lipase measures generally reflect a
simple pattern of significant parent-offspring and sibling correlations
and no significant spouse resemblance, suggesting a primarily genetic
etiology. Spouse resemblance is significant for
triglyceride and hepatic lipase, suggesting that there may
be some common environmental factors in addition to genetic factors
influencing these traits. For HDL-cholesterol sibling
resemblance is larger than that for parent-offspring pairs, suggesting
some additional shared sibship factors influencing HDL levels. Finally,
the familial resemblance for lipoprotein lipase appears to be
sex-specific (female pairs > opposite-sex > male
pairs).
|
The maximum heritabilities derived from the most parsimonious models
are also given in Table 4. These estimates include both genetic and
common environmental sources of variance and are adjusted for the
degree of spouse resemblance if significant. The estimates range from
40% for HL to 83% for HDL-cholesterol. For LPL, which
exhibited significant sex differences in the familial correlations, the
heritability estimates reach 30% when derived from male correlations
(father-son and son-son), 44% when derived from opposite sex
correlation (father-daughter, mother-son and son-daughter), and 76%
when derived from female correlations (mother-daughter and
daughter-daughter) with an average heritability of 50%.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The results of the present study indicate that both plasma lipid and lipoprotein concentrations and plasma postheparin LPL and HL activities strongly aggregate in families. Although genetic and cultural transmission cannot be quantified separately based only on familial correlations computed in intact nuclear families without any index of familial environment, as in the present study, genetic and environmental inferences can be made by inspection of the pattern of familial correlations. For example, a pattern of significant correlations among siblings and between parents and offspring, but not between spouses (who presumably share no genes by immediate descent) suggest that the familial aggregation is likely to be due to genetic factors. This is exactly what was found in the present study for total plasma cholesterol, HDL-cholesterol and LDL-cholesterol levels. For triglyceride concentrations, significant spouse resemblance was observed in addition to parent-offspring and sibling correlations.
The heritability estimates reported in this study are within the range of those reported in several other family studies9,10,12,33–40 with average heritabilities (range) of 55% (39% to 71%) for total cholesterol, 52% (28% to 80%) for HDL-cholesterol, 49% (23% to 72%) for LDL-cholesterol, and 32% (13% to 61%) for triglycerides. The heritabilities reported in the present study tend to be higher than the average heritabilities computed from these family studies, which could be explained by two factors. First, the heritabilities reported here should be considered as "maximal" heritabilities as no distinction can be made between genetic and cultural inheritance with the approach used in the present study. Since common familial environment accounts for up to 20% of the variance of plasma lipids and lipoproteins,9,10,13 one cannot exclude the contribution of cultural inheritance as a determinant of the familial aggregation observed in this study, despite the absence of spouse correlation. Second, subjects in the HERITAGE Family study were recruited to be "sedentary" at baseline, thus providing a unique control over an important environmental factor that could contribute to interindividual differences in blood lipids and lipoproteins, ie, physical activity level. Several studies have shown that plasma lipid and lipoprotein levels are affected by regular exercise and some of the protective effect of physical activity against CHD has been postulated to be mediated by the beneficial effects on the lipid and lipoprotein profile.41–46 Such a control over the level of physical activity could reduce the phenotypic variance and thus lead to higher heritability estimates.
A unique feature of the present study is the investigation of the familial resemblance in postheparin plasma LPL and HL activities. Our results suggest that interindividual differences in HL and LPL activities are genetically determined as indicated by average heritabilities of 40% and 50%, respectively. Besides molecular studies, the only evidence for a role of genetic factors in lipase activities come from twin studies. In one study based on a small number MZ and DZ male twin pairs, a significant genetic effect was reported for post-heparin plasma HL, but not for LPL.24 The other studies are based on LPL activity measured in the adipose tissue. In one study in which LPL activity was measured in suprailiac adipose tissue samples obtained from 28 pairs of MZ twins and 25 pairs of DZ twins, Bouchard et al47 reported a higher correlations in MZ twins (r=0.65) compared to DZ twins (r=0.10), suggesting a highly significant heritability for LPL activity. Evidence from twin studies also suggest that the response of adipose tissue LPL activity to exercise or overfeeding is genetically determined. For example, a greater within pair resemblance in 11 pairs of MZ twins (r=0.87) compared to 10 pairs of DZ twins (r=0.51) was reported in the response of the suprailiac adipose tissue LPL activity to a prolonged (90 minutes) single bout of exercise.48 These results suggest a role for genetic factors in the acute response of adipose tissue LPL to exercise. Furthermore, a significant MZ intrapair resemblance (r=0.82) was also observed in the response of the adipose tissue (suprailiac depot) LPL activity to short-term (22 days) overfeeding.49 These twin studies suggest a role for genetic factors in the regulation of adipose tissue LPL activity.
Another novel finding of the present study is the presence of significant sex differences in the familial correlations of LPL, resulting in higher heritabilities in female pairs (h2=76%), intermediate heritabilities in opposite-sex pairs (h2=44%) and lower heritabilities in male pairs (h2=30%). Several studies have shown that women exhibit a lipoprotein profile associated with a reduced risk of CHD, particularly because of their higher plasma levels of HDL-cholesterol. Moreover, post heparin LPL activity was reported to be higher in women that in men50,51 and to be positively correlated with circulating levels of HDL-cholesterol.16,52 These observations suggest that the protective lipid profile observed in women could be to some extent explained by the gender differences in LPL activity, as recently shown in a study based on measurements of femoral adipose tissue LPL activity in a sample of 14 premenopausal women and 17 men.29 Our finding of higher heritability levels in females compared to males for LPL activity indicates that the genetic factors affecting LPL activity are sex-specific and suggests that the sex differences observed in LPL activity and in HDL-cholesterol levels could be genetically determined.
In summary, the results of the present family study indicate that genetic factors contribute significantly to the familial resemblance observed in plasma lipid and lipoprotein levels and in plasma postheparin LPL and HL activities in sedentary individuals with heritability estimates ranging from 40% to 83%. They also reveal the presence of sex differences in the heritabilities of LPL with higher heritabilities in females compared to males. Further genetic studies testing for the presence of major gene effects and investigating the pleiotropic effects between plasma postheparin triglyceride lipase activities and lipoprotein levels will be needed to better understand the genetic basis of lipid and lipoprotein metabolism.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
The HERITAGE study is supported by the NHLBI through the following grants: HL45670 (C. Bouchard, PI), HL47323 (A.S. Leon, PI), HL47317 (D.C. Rao, PI), HL47327 (J.S. Skinner, PI), and HL47321 (J.H. Wilmore, PI). Jack H. Wilmore is supported by the Margie Gurley Seay Centennial Professorship and Arthur Leon is partially supported by the Henry L. Taylor endowed Professorship in Exercise Science and Health Enhancement.
Thanks are expressed to all the co-principal investigators, investigators, co-investigators, local project coordinators, research assistants, laboratory technicians, and secretaries who are contributing to the study. Finally, the entire HERITAGE consortium is very thankful to those hard-working participating families whose involvement alone demonstrates the feasibility of this study.
Received February 5, 1997; accepted May 8, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Wallace RB, Anderson RA. Blood lipids, lipid-related measures, and the risk of atherosclerotic cardiovascular disease. Epidemiol Rev. 1987;9:95–119.
2. Breckenridge CW. The role of lipoproteins and apolipoproteins in prediction of coronary heart disease risk. Clin Invest Med. 1990;13:196–201.[Medline] [Order article via Infotrieve]
3. Zemel PC, Sowers JR. Relation between Lipids and Atherosclerosis: Epidemiologic Evidence and Clinical Implications. Am J Cardiol. 1990;66:7-I–12-I.
4.
Austin MA. Plasma triglyceride and
coronary heart disease. Arterioscler. Thromb. 1991;11:2–14.
5. Loscalzo J, Sniderman A. Cardiovascular disease and hyperlipidaemia. Current Opin Lipidol. 1993;4:273–276.
6. Holme I. Relation of coronary heart disease incidence and total mortality to plasma cholesterol reduction in randomised trials: use of meta-analysis. Br Heart J. 1993;69:S42–S47.
7. Barth JD. Lipoproteins and the progression/regression of atherosclerosis. Baillière's Clinical Endocrinology and Metabolism. 1995;9:849–866.
8.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford
JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR,
Braunwald E. The effect of pravastatin on coronary
events after myocardial infarction in patients with average
cholesterol levels. N Engl J Med. 1996;335:1001–1009.
9. Rao DC, Morton NE, Gulbrandsen CL, Rhoads GG, Kagan A, Yee S. Cultural and biological determinants of lipoprotein concentrations. Ann Hum Genet Lond. 1979;42:467–477.
10. Rao DC, Laskarzewski PM, Morrison JA, Khoury P, Kelly K, Wette R, Russell J, Glueck CJ. The Cincinnati Lipid Research Clinic family study: Cultural and biological determinants of lipids and lipoprotein concentrations. Am J Hum Genet. 1982;34:888–903.[Medline] [Order article via Infotrieve]
11. Segal P, Rifkind BM, Schull WJ. Genetic factors in lipoprotein variation. Epidemiol Rev. 1982;4:127–160.
12. Namboodiri KK, Kaplan EB, Heuch I, Elston RC, Green PP, Rao DC, Laskarzewski PM, Glueck CJ, Rifkind BM. The collaborative Lipid Research Clinics family study: Biological and cultural determinants of familial resemblance for plasma lipids and lipoproteins. Genet Epidemiol. 1985;2:227–254.[Medline] [Order article via Infotrieve]
13. Sing CF, Boerwinkle EA. Genetic architecture of inter-individual variability in apolipoprotein, lipoprotein and lipid phenotypes. In: Bock G, Collins GM, eds. Molecular approaches to human polygenic disease. v. 130. New York: John Wiley & Sons, 1987:99–127.
14.
Heller DA, deFaire U, Pedersen NL, Dahlen G, McClean
GE. Genetic and environmental influences on serum lipid levels in
twins. N Engl J Med. 1993;328:1150–1156.
15. Taskinen MR, Nikkila EA. High-density lipoprotein subfractions in relation to lipoprotein lipase activity of tissues in man - Evidence for reciprocal regulation of HDL2 and HDL3 levels by lipoprotein lipase. Clin Chemi Acta. 1981;112:325–332.
16. Kekki M. Lipoprotein-lipase action determining plasma high density lipoprotein cholesterol level in adult normolipaemics. Atherosclerosis. 1980;37:143–150.[Medline] [Order article via Infotrieve]
17. Kuusi T, Saarinen P, Nikkila EA. Evidence for the role of hepatic endothelial lipase in the metabolism of plasma high density lipoproteins in men. Atherosclerosis. 1980;36:589–593.[Medline] [Order article via Infotrieve]
18.
Després J-P, Ferland M, Moorjani S, Nadeau A,
Tremblay A, Lupien PJ, Thériault G, Bouchard C. Role of
hepatic-triglyceride lipase activity in the association
between intra-abdominal fat and plasma HDL cholesterol in
obese women. Arteriosclerosis. 1989;9:485–492.
19. Lalouel JM, Wilson DE, Iverius PH. Lipoprotein lipase and hepatic triglyceride lipase: molecular and genetic aspects. Current Opin Lipidol. 1992;3:86–95.
20.
Gagné E, Genest J, Zhang H, Clarke LA, Hayden MR.
Analysis of DNA changes in the LPL gene in patients with
familial combined hyperlipidemia. Arterioscler
Throm. 1994;14:1250–1257.
21.
Mattu RK, Needham EWA, Morgan R, Rees A, Hackshaw AK,
Stocks J, Elwood PC, Galton DJ. DNA variants at the LPL gene locus
associate with angiographicallly severity of
atherosclerosis and serum lipoprotein levels in a Welsh
population. Arterioscler Thromb. 1994;14:1090–1097.
22.
Gerdes C, Gerdes LU, Hansen PS, Faergeman O.
Polymorphisms in the lipoprotein lipase gene and their associations
with plasma lipid concentrations in 40-year-old Danish men.
Circulation. 1995;92:1765–1769.
23. Georges J-L, Régis-Bailly A, Salah D, Rakotovao R, Siest G, Visvikis S, Tiret L. Family study of lipoprotein lipase gene polymorphism and plasma triglyceride levels. Genet Epidemiol. 1996;13:179–192.[Medline] [Order article via Infotrieve]
24.
Kuusi T, Kesäniemi A, Vuoristo M, Miettinen TA,
Koskenvuou M. Inheritance of high density lipoprotein and lipoprotein
lipase and hepatic lipase activity.
Arteriosclerosis. 1987;7:421–425.
25. Bouchard C, Leon AS, Rao DC, Skinner JS, Wilmore JH, Gagnon J. Aims, design and measurement protocol. Med Sci Sports Exerc. 1995;27:721–729.[Medline] [Order article via Infotrieve]
26. Havel RJ, Eder H, Bragdow HF. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955;34:1345–1353.
27. Burstein, M, Samaille J. Sur un dosage rapide du cholestérol lié aux b-lipoprotéines du sérum. J Clin Chim Acta. 1960;5:609–610.
28. Nilsson-Ehle P, Ekman R. Specific assays for lipoprotein lipase activities of post-heparin plasma. In Peeters H, (ed). Protides of biological fluids. Oxford: Pergamon Press, 1978:243–246.
29. St-Amand J, Després J-P, Lemieux S, Lamarche B, Moorjani S, Prud'homme D, Bouchard C, Lupien PJ. Does lipoprotein or hepatic lipase activity explain the protective lipoprotein profile of premenopausal women. Metabolism. 1995;44:491–498.[Medline] [Order article via Infotrieve]
30. Gagnon J, Province MA, Bouchard C, Leon AS, Skinner JS, Wilmore JH, and Rao DC. The HERITAGE Family Study: quality assurance and quality control. Ann. Epidemiol. 1996;6:520–529.[Medline] [Order article via Infotrieve]
31. Province MA, Rao DC. General purpose model and a computer program for combined segregation and path analysis (SEGPATH): Automatically creating computer programs from symbolic language model specifications. Genet Epidemiol. 1995;12:203–219.[Medline] [Order article via Infotrieve]
32. Akaike H. A new look at the statistical model identification. IEEE Trans Automat Control. 1976;19:716–723.
33. Rao DC, Morton NE, Clueck CJ, Laskarzewski PM, Russell JM. Heterogeneity between populations for multifactorial inheritance of plasma lipids. Am J Hum Genet. 1983;35:468–483.[Medline] [Order article via Infotrieve]
34.
Laskarzewski PM, Clueck CJ, Rao DC. Family resemblance
for plasma lipids and lipoprotein concentrations in blacks.
Arteriosclerosis. 1984;4:65–69.
35. Hamsten A, Iselius L, Dahlen G, deFaire U. Genetic and cultural inheritance of serum lipids, low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B. Atherosclerosis. 1986;60:199–208.[Medline] [Order article via Infotrieve]
36. Friedlander Y, Kark JD, Stein Y. Heterogeneity in multifactorial inheritance of plasma lipids and lipoproteins in ethnically diverse families in Jerusalem. Genet Epidemiol. 1986;3:95–112.[Medline] [Order article via Infotrieve]
37. Bucher KD, Friedlander Y, Kaplan EB, Namboodiri KK, Kark JD, Eisenberg S, Stein Y, Rifkind BM. Biological and cultural sources of familial resemblance in plasma lipids: A comparison between North America and Israel. The Lipid Research Clinics program. Genet Epidemiol. 1988;5:17–33.[Medline] [Order article via Infotrieve]
38.
Hunt SC, Hasstedt SJ, Kuida H, Stults BM, Hopkins PN,
Williams RR. Genetic heritability and common environmental components
of resting and stressed blood pressures, lipids, and body mass index in
Utah pedigrees and twins. Am J Epidemiol. 1989;129:625–638.
39.
Pérusse L, Després J-P, Tremblay A, Lcblanc
C, Talbot J, Allard C, Bouchard C. Genetic and environmental
determinants of serum lipids and lipoproteins in French Canadian
families. Arteriosclerosis. 1989;9:308–318.
40. Rice T, Vogler GP, Perry TS, Laskarzewski PM, Rao DC. Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Iowa lipid research clinics family study. Hum Hered. 1991;41:107–121.[Medline] [Order article via Infotrieve]
41. Haskell WL. Exercise-induced changes in plasma lipids and lipoproteins. Prev Med. 1984;13:23–36.[Medline] [Order article via Infotrieve]
42. Leon AS. Effects of exercise conditioning on physiologic precursors of CHD. J Cardiopul Rehab. 1991;11:46–57.
43. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med. 1991;325:461–466.[Abstract]
44. MacAuley D. Exercise, cardiovascular disease and lipids. Br J Clin Pract. 1993;47:323–327.[Medline] [Order article via Infotrieve]
45. Durstine JL, Haskell WL. Effects of exercise training on plasma lipids and lipoproteins. Exer Sports Sci Rev. 1994;22:477–521.
46. Després J-P, Lamarche B. Low-intensity endurance exercise training, plasma lipoproteins and the risk of coronary heart disease. J Intern Med. 1994;236:7–22.[Medline] [Order article via Infotrieve]
47. Bouchard C. Inheritance of fat distribution and adipose tissue metabolism. In: Vague J., ed. Metabolic complications of human obesity. Elsevier Science Publishers, 1985:87–96.
48. Savard R, Bouchard C. Genetic effects in the response of adipose tissue lipoprotein lipase activity to prolonged exercise: a twin study. Int J Obes. 1990;14:771–777.[Medline] [Order article via Infotrieve]
49.
Poehlman ET, Després J-P, Marcotte M, Tremblay A,
Theriault G, Bouchard C. Genotype dependency for adaptation in
adipose tissue metabolism after short-term overfeeding.
Am J Physiol. 1986;250:E480–E485.
50. Boberg J. Heparin-released blood plasma lipoprotein lipase activity in patients with hyperlipoproteinemia. Acta Med Scand. 1972;191:97–102.[Medline] [Order article via Infotrieve]
51. Huttunen JK, Ehnholm C, Kekki M, Nikkila EA. Post-heparin plasma lipoprotein lipase and hepatic lipase in normal subjects and in patients with hypertriglyceridemia: correlations to sex, age, and various parameters of triglyceride metabolism. Clin Sci Mol Med. 1976;50:249–260.[Medline] [Order article via Infotrieve]
52. Pouliot M-C, Després J-P, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. Regional variation in adipose tissue lipoprotein lipase activity: association with plasma high density lipoprotein levels. Eur J Clin Invest. 1991;21:398–405.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. Di Castelnuovo, G. Quacquaruccio, M. B. Donati, G. de Gaetano, and L. Iacoviello Spousal Concordance for Major Coronary Risk Factors: A Systematic Review and Meta-Analysis Am. J. Epidemiol., January 1, 2009; 169(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. M. Heid, E. Boes, M. Muller, B. Kollerits, C. Lamina, S. Coassin, C. Gieger, A. Doring, N. Klopp, R. Frikke-Schmidt, et al. Genome-Wide Association Analysis of High-Density Lipoprotein Cholesterol in the Population-Based KORA Study Sheds New Light on Intergenic Regions Circ Cardiovasc Genet, October 1, 2008; 1(1): 10 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Hodoglugil, S. Tanyolac, D. W. Williamson, Y. Huang, and R. W. Mahley Apolipoprotein A-V: a potential modulator of plasma triglyceride levels in Turks J. Lipid Res., January 1, 2006; 47(1): 144 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yu, D. F. Wyszynski, D. M. Waterworth, S. D. Wilton, P. J. Barter, Y. A. Kesaniemi, R. W. Mahley, R. McPherson, G. Waeber, T. P. Bersot, et al. Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia J. Lipid Res., October 1, 2005; 46(10): 2202 - 2213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Teran-Garcia, N. Santoro, T. Rankinen, J. Bergeron, T. Rice, A. S. Leon, D.C. Rao, J. S. Skinner, R. N. Bergman, J.-P. Despres, et al. Hepatic Lipase Gene Variant -514C>T Is Associated With Lipoprotein and Insulin Sensitivity Response to Regular Exercise: The HERITAGE Family Study Diabetes, July 1, 2005; 54(7): 2251 - 2255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Feitosa, I. B. Borecki, T. Rankinen, T. Rice, J.-P. Despres, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, C. Bouchard, et al. Evidence of QTLs on chromosomes 1q42 and 8q24 for LDL-cholesterol and apoB levels in the HERITAGE Family Study J. Lipid Res., February 1, 2005; 46(2): 281 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jacqmain, E. Doucet, J.-P. Despres, C. Bouchard, and A. Tremblay Calcium intake, body composition, and lipoprotein-lipid concentrations in adults Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1448 - 1452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J J McCarthy, T Lehner, C Reeves, D J Moliterno, L K Newby, W J Rogers, and E J Topol Association of genetic variants in the HDL receptor, SR-B1, with abnormal lipids in women with coronary artery disease J. Med. Genet., June 1, 2003; 40(6): 453 - 458. [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Newman, M. Abney, H. Dytch, R. Parry, M. S. McPeek, and C. Ober Major loci influencing serum triglyceride levels on 2q14 and 9p21 localized by homozygosity-by-descent mapping in a large Hutterite pedigree Hum. Mol. Genet., January 15, 2003; 12(2): 137 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Pennacchio, M. Olivier, J. A. Hubacek, R. M. Krauss, E. M. Rubin, and J. C. Cohen Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels Hum. Mol. Genet., November 15, 2002; 11(24): 3031 - 3038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Coon, M. F. Leppert, J. H. Eckfeldt, A. Oberman, R. H. Myers, J. M. Peacock, M. A. Province, P. N. Hopkins, and G. Heiss Genome-Wide Linkage Analysis of Lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1969 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Peacock, D. K. Arnett, L. D. Atwood, R. H. Myers, H. Coon, S. S. Rich, M. A. Province, and G. Heiss Genome Scan for Quantitative Trait Loci Linked to High-Density Lipoprotein Cholesterol: The NHLBI Family Heart Study Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1823 - 1828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C Seidell, L. Perusse, J.-P. Despres, and C. Bouchard Waist and hip circumferences have independent and opposite effects on cardiovascular disease risk factors: the Quebec Family Study Am. J. Clinical Nutrition, September 1, 2001; 74(3): 315 - 321. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. Garenc, L. Perusse, J. Bergeron, J. Gagnon, Y. C. Chagnon, I. B. Borecki, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, et al. Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study J Appl Physiol, September 1, 2001; 91(3): 1334 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. B. Harrap, M. Stebbing, J. L. Hopper, H. N. Hoang, and G. G. Giles Familial Patterns of Covariation for Cardiovascular Risk Factors in Adults: The Victorian Family Heart Study Am. J. Epidemiol., October 15, 2000; 152(8): 704 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Friedlander, P. J. Talmud, K. L. Edwards, S. E. Humphries, and M. A. Austin Sib-pair linkage analysis of longitudinal changes in lipoprotein risk factors and lipase genes in women twins J. Lipid Res., August 1, 2000; 41(8): 1302 - 1309. [Abstract] [Full Text]
|
|
|
|
|
|
P. Couture, J. D. Otvos, L. A. Cupples, C. Lahoz, P. W. F. Wilson, E. J. Schaefer, and J. M. Ordovas Association of the C-514T Polymorphism in the Hepatic Lipase Gene With Variations in Lipoprotein Subclass Profiles : The Framingham Offspring Study Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 815 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. De Oliveirae Silva, M. Kong, Z. Han, C. Starr, E. M. Kass, S.-H. H. Juo, D. Foster, H. M. Dansky, M. Merkel, K. Cundey, et al. Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females J. Lipid Res., July 1, 1999; 40(7): 1211 - 1221. [Abstract] [Full Text]
|
|
|
|
|
|
L. Nie, J. Wang, L. T. Clark, A. Tang, G. L. Vega, S. M. Grundy, and J. C. Cohen Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence postheparin plasma hepatic lipase activity J. Lipid Res., May 1, 1998; 39(5): 1127 - 1130. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||