(Circulation. 2000;101:2777.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Cardiovascular Disease Mortality in Familial Forms of Hypertriglyceridemia: A 20-Year Prospective Study
From the Department of Epidemiology (M.A.A, K.L.E., C.M.B.) and the Department of Biostatistics, School of Public Health and Community Medicine (B.M.); the Division of General Internal Medicine, Department of Medicine, School of Medicine, (M.J.M.); the Departments of Medicine, Epidemiology, and Health Services, Cardiovascular Health Research Unit, Schools of Medicine and Public Health and Community Medicine (B.M.P.); the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, School of Medicine (J.D.B.); and the Division of Medical Genetics, Department of Medicine and Department of Genetics (A.G.M.); University of Washington, Seattle.
Correspondence to Melissa A. Austin, PhD, Department of Epidemiology, Box 357236, University of Washington, Seattle, WA 98195-7236. E-mail maustin{at}u.washington.edu
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Abstract |
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Background—Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are 2 of the most common familial forms of hyperlipidemia. There is a paucity of prospective data concerning the risk of cardiovascular disease (CVD) in such families. The purposes of this study were to estimate 20-year total and CVD mortality risk among relatives in these families and to evaluate plasma triglyceride as a predictor of death.
Methods and Results—The study was based on lipid and medical history data from 101 families ascertained in 2 studies conducted in the early 1970s. Vital status and cause of death was determined during 1993 to 1997 for 685 family members, including first-degree relatives of the probands and spouse control subjects. Compared with spouse control subjects, 20-year CVD mortality risk was increased among siblings and offspring in FCHL (relative risk 1.7, P=0.02) after adjustment for baseline covariates. In FHTG families, the relative risk was also 1.7 but was not statistically significant (P=0.39). Baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in FHTG families (relative risk 2.7, P=0.02) but not in FCHL families (relative risk 1.5, P=0.16) after adjustment for baseline covariates.
Conclusions—This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and illustrates the need for effective prevention strategies in this group. Baseline triglyceride level predicted subsequent CVD mortality among relatives in FHTG families, adding to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.
Key Words: cardiovascular diseases • follow-up studies • hyperlipoproteinemia • lipids • mortality
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Introduction |
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The familial forms of hypertriglyceridemia, familial combined hyperlipidemia (FCHL) and familial "monogenic" hypertriglyceridemia (FHTG), are 2 common forms of familial hyperlipidemia among families with coronary heart disease (CHD).1 2 3 4 These well-established clinical disorders of lipid and lipoproteins were first characterized at the University of Washington in the early 1970s. The characteristics and estimated frequencies of these familial disorders were described1 2 5 6 on the basis of families of myocardial infarction survivors and families of hypertriglyceridemic patients without clinical CHD. Similar studies were performed in Finland during the same time period.7
There is a paucity of information about the long-term risk of cardiovascular disease (CVD) in the familial forms of hypertriglyceridemia. Cross-sectional data from the Seattle studies consistently demonstrated an increased prevalence of CHD among relatives of probands in families with FCHL.1 2 However, for FHTG, increased familial risk was found among families ascertained through myocardial infarction survivors2 but not among families ascertained through probands free of coronary artery disease.1 The incidence of CVD in these familial disorders has never been evaluated.
The common feature of FCHL and FHTG is elevated plasma triglyceride levels in relatives. Although the importance of elevated plasma cholesterol as a risk factor for CHD is indisputable,8 9 the role of triglyceride has been controversial for >3 decades10 11 and has been referred to as the "forgotten risk factor."12 However, accumulating epidemiological evidence13 14 strongly suggests that elevated triglyceride is associated with increased risk of CVD independent of HDL cholesterol. Recent findings from the Copenhagen Male Study revealed that increasing baseline triglyceride was associated with higher incidence of ischemic heart disease during an 8-year follow-up within each tertile of HDL cholesterol.15 The association between triglyceride levels and risk of CVD has never been studied prospectively in the familial forms of hypertriglyceridemia.
The purpose of this study was to evaluate 20-year total mortality and cardiovascular mortality risk in families with FCHL and FHTG on the basis of 101 families originally studied in the early 1970s. Two questions were addressed: (1) is there increased risk for total mortality and for CVD mortality among first-degree relatives of probands in FCHL and FHTG families compared with spouse control subjects, and (2) does baseline triglyceride predict subsequent cardiovascular mortality among relatives in hypertriglyceridemic families?
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Methods |
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Family Ascertainment
This analysis is based on 2 baseline family studies, both conducted at the University of Washington in the early 1970s. Baseline study 12 identified families with FCHL or FHTG ascertained through probands who were myocardial infarction survivors; baseline study 21 ascertained families through probands with hypertriglyceridemia but with no clinical evidence of coronary disease. Twenty-year follow-up on 101 families from baseline studies 1 and 2 are reported here. Of these, 62% were classified as FCHL and 38% were classified as FHTG at baseline.
Eligible family members for the mortality follow-up study were
first-degree relatives of probands (parents, siblings, and offspring)
and spouses of probands, siblings, and offspring, 
18 years of age,
who participated in 1 of the 2 baseline studies. This totaled 718
family members, including 435 first-degree relatives of probands and
283 spouse control subjects (Table 1
).
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Baseline Data
Family pedigrees were available from the baseline
studies.1 2 Lipid determinations were based on fasting
blood samples. In the early 1970s, total cholesterol was
measured by AutoAnalyzer II method N-24a, and
triglyceride level was determined by a semiautomated method
modified from the procedures of Carlson,16 17 also with
the use of the AutoAnalyzer. The triglyceride assay
has been replaced with new methodology,18 and a comparison
of the methods demonstrated a linear relation between the 2 sets of
triglyceride values (Brunzell, unpublished data). This
relation was used to convert the baseline triglyceride
values to be comparable with current methodology. At baseline, study
subjects completed a medical history questionnaire, including birth
date, sex, smoking status, and self-reported diabetes, hypertension,
and prior myocardial infarction.
Follow-Up Procedures, Vital Status, and Cause-of-Death
Classification
Study subjects were designated "confirmed alive" at
follow-up if they agreed to participate in the study by completing a
personal medical history form and/or providing a blood sample or if
they personally declined participation. Living subjects not contacted
in person were categorized as "reported alive" on the basis of
information supplied by family members. Deceased study subjects were
designated "confirmed dead" on the basis of death certificates. If
a copy of the death certificate could not be obtained, subjects were
designated "reported dead" on the basis of information from family
members. Vital status could not be determined for 29 (4%) study
subjects, and these were excluded. For the total mortality
analysis, confirmed and reported deceased categories were
combined, as were the confirmed living and reported living
categories.
A modified version of the Cardiovascular Health Study protocol was used for cause-of-death classification.19 All medical records were prescreened by a research assistant and were blinded to the deceased subject’s lipid levels, presence or absence of hyperlipidemia diagnosis, family history of hyperlipidemia, and to all baseline study data and family relationship (relative of proband or unrelated spouse). Cause of death was classified for each deceased study subject by the study physician (M.J.M.), based on all available medical records. Cardiovascular death was defined as fatal myocardial infarction, CHD, atherosclerotic cerebral vascular accident (stroke), or peripheral vascular disease (aortic aneurysm, revascularization procedures). These categories were combined as CVD death, and deaths not attributed to CVD were combined as non-CVD deaths. Nineteen subjects whose deaths were not confirmed by death certificate were excluded from the CVD mortality analysis.
All study participants provided written informed consent at the time they were enrolled in the baseline studies in the early 1970s. For the follow-up study, the University of Washington Institutional Review Board approved the methods used to recontact living family members and to obtain records on deceased subjects.20
Statistical Analysis
The mortality analyses were performed with the use of
Cox regression for censored survival data based on person-years of
follow-up.21 22 The time variable was the subject’s
age, so that each subject entered the follow-up analysis at the
age he or she was ascertained to be in the early 1970s. Age at
follow-up, defined as age at death for deceased subjects and age at
study participation, refusal, or date reported living for living
subjects, was the end point age for the analysis. With the use
of this approach, all reported relative risks are adjusted for age.
Since the survival ages of members of the same family may be correlated
as the result of genetic or environmental similarities, modified
standard error estimators that account for correlations between members
of the same kindred were used.23 All relative risks were
also adjusted for covariates with the use of data from the baseline
medical history questionnaire. For covariates in which the assumption
of proportional hazards was not met, stratification adjustment was
used.
Twenty-one study subjects were missing baseline medical history data, and these subjects were excluded from the survival analysis. Fifteen study subjects were missing baseline triglyceride and cholesterol determinations and were excluded from analyses that include these variables. Because the frequency distribution of triglyceride was skewed, a natural log transformation was used, and relative risks for a 1-unit increase in log triglyceride are reported.
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Results |
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Baseline Data
Baseline characteristics of the 718 eligible study subjects are shown in Table 1
. Among the first-degree relatives of probands,
approximately half of the study subjects were women, whereas the
proportions of female spouses were somewhat higher. Among the
first-degree relatives, overall average ages varied from 46 to 48
years. By definition, mean baseline triglyceride levels
were higher among relatives than spouse control subjects in the FCHL
families and in the FHTG families (Table 1). Also, as expected,
total plasma cholesterol levels were higher among relatives
in FCHL families compared with both spouse control subjects and with
relatives in FHTG families. Prior myocardial infarction at baseline was
less frequent among both relatives and spouses in FHTG families
compared with FCHL families. The prevalence of self-reported diabetes
was higher among first-degree relatives in both types of families
compared with spouse control subjects.24
20-Year Mortality Among Relatives in FCHL and FHTG
Families
In the FCHL families, 36% of siblings and offspring of probands
were dead at follow-up compared with 29% of spouse control subjects in
the same generations. On the basis of on the Cox regression model, a
40% increase in total mortality risk was seen among siblings and
offspring compared with spouse control subjects, adjusting for sex,
baseline study, and diabetes, hypertension, smoking, and prior
myocardial infarction at baseline (Table 2). Among the FHTG families, the
proportion of deceased siblings and offspring at follow-up was slightly
lower than for spouse control subjects, and the relative risk for total
mortality did not differ statistically from 1.0
(P=0.67).
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Siblings and offspring in FCHL families were at a 70% increased risk of CVD mortality compared with spouse control subjects (relative risk 1.7, 95% CI 1.1 to 2.7, P=0.02), adjusting for sex, baseline study, and diabetes, hypertension, smoking, and prior myocardial infarction at baseline. Among FHTG families, the relative risk was also 1.7 but was not statistically significant (95% CI 0.50 to 5.9, P=0.39), possibly because of the smaller sample size.
Triglyceride as a Risk Factor for CVD
Mortality
Baseline triglyceride was a significant predictor of
subsequent CVD mortality among families in this study. As shown in
Figure 1, a positive association was seen
between increasing baseline levels of triglyceride and
age-standardized CVD mortality rate for relatives in all families.
Adjusting for age, sex, baseline study, baseline covariates, and type
of family, a 1–natural log unit increase in triglyceride
resulted in a statistically significant relative risk of 1.9
(P=0.001) for cardiovascular death among
first-degree relatives of probands (Table 3). This relative risk was reduced to 1.7
after adjusting for total cholesterol at baseline but
remained statistically significant (P=0.009). There was
strong evidence that the relative risk for cholesterol
varied with attained age, ranging from 2.9 at age 20 years to 0.96 at
age 80 years, with adjustment for baseline covariates.
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Since there were 17 family members with fasting triglyceride values >500 mg/dL, the analysis was repeated excluding these study subjects. The magnitude of the associations remained similar, although probability values were larger. Furthermore, in a sensitivity analysis, the results were only altered by the most extreme and implausible assumptions about eligible study subjects whose vital status or cause of death could not be determined.25
The relation between triglyceride and age-standardized
rates for CVD mortality appeared to be different for relatives in FHTG
families and FCHL families (Figure 2).
After adjustment for covariates, the magnitude of the relation between
triglyceride and CVD mortality also appeared to be
different for the FCHL and FHTG, although relative risk estimates were
not statistically significantly different (relative risk 1.7,
P=0.06, and 2.9, P<0.001, respectively, Table 3). After adjustment for baseline cholesterol
levels, the association of baseline triglyceride and CVD
mortality remained statistically significant for FHTG relatives but not
for FCHL relatives. Deaths among FCHL relatives occurred over a wide
age range, including premature deaths, whereas none of the CVD deaths
were premature for FHTG relatives. There was little evidence for
differences among study subjects from the 2 baseline studies (data not
shown).
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Discussion |
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This 20-year, prospective study of hypertriglyceridemic families demonstrated that first-degree relatives of probands in families with FCHL were at a statistically significant (70%) increased risk of CVD mortality compared with spouse control subjects. Because FCHL is one of the most common forms of hyperlipidemia among families with CHD, identifying FCHL families and implementing effective risk factor intervention strategies could have an important impact on CVD prevention. A similar but nonsignificant increased risk of cardiovascular mortality was seen among relatives in FHTG families. A larger sample of families or longer follow-up time will be needed to resolve this equivocal result for FHTG. Sample sizes also precluded determining whether the results differed for the 2 baseline studies.
Among FCHL families, the relative risk estimates reported here may be conservative if an autosomal dominant mode of inheritance is operating, as was proposed in baseline study 1.2 Under such a genetic model, only approximately half of the first-degree relatives of probands would be expected to carry a proposed disease susceptibility allele, reducing the apparent risk among all relatives combined in comparison with control subjects. Relative risk estimates also could be conservative if spouses in these families are at increased risk of CVD as the result of assortative mating of lifestyle and risk factors,26 although the sex differential inherent in using spouse control subjects could introduce other biases.
The original classifications that defined familial hyperlipidemias in the 2 baseline studies were used in this analysis. Since that time, FCHL has been characterized by an overproduction of apolipoprotein B and has been associated with small, dense LDL.27 28 29 30 Both of these lipid disorders are risk factors for CHD31 32 33 34 35 and may underlie at least a portion of the increased familial risk of CVD mortality. Individuals with FHTG have been found to have increased hepatic triglyceride synthesis with secretion of triglyceride-rich lipoproteins.27 30 The increased triglyceride synthesis is associated with hepatic colic acid synthesis,36 37 possibly secondary to a partial block in intestinal bile acid absorption. Like bile acid–binding resins, this proposed block also may increase triglyceride synthesis. Although the association of baseline triglyceride and CVD mortality among relatives from FHTG families in this study was statistically significant and independent of total cholesterol (relative risk 2.7, P=0.02), how these metabolic processes might alter risk for CVD remains to be determined.
The genetic differences between FCHL and FHTG are not fully understood. Although no studies to date have investigated the molecular basis of FHTG, 2 recent reports based on families ascertained in Finland and in the Netherlands have suggested the existence of novel genes for FCHL on human chromosomes 138 and 11,39 respectively. Other studies have proposed that the clustering of lipid abnormalities in FCHL may be related to the insulin resistance syndrome and that mutations in the lipoprotein lipase gene and the hormone-sensitive lipase gene may be involved in FCHL.40 41 42 43
Baseline plasma triglyceride levels predicted subsequent CVD mortality among all relatives in these hypertriglyceridemic families (relative risk 1.9 for a 1–log unit increase in triglyceride [mg/dL]), and this result remained statistically significant after adjustment for total cholesterol. These relative risks are similar to those reported from population-based studies, including the Lipid Research Clinics Follow-up Study,44 the Physicians’ Health Study,31 and a meta-analysis of population-based, prospective epidemiological studies.13 Furthermore, the results presented here resemble 5-year mortality data recently reported from the Benzafibrate Infarction Prevention Registry, in which the 4th and 5th quintiles of triglyceride were associated with increased risk of CHD mortality among both men and women.45 Because HDL cholesterol and apolipoprotein measurements were not available at the time of the baseline Seattle studies, the findings reported here must be interpreted cautiously. Even so, clinical trials are needed to determine if lowering triglyceride levels with the use of statins and/or fibrates, especially among patients with combined hyperlipidemia,46 47 will reduce subsequent risk of CVD.
In conclusion, this prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and illustrates the need for effective prevention strategies in this group. Baseline triglyceride levels predicted subsequent CVD mortality among relatives in FHTG families, adding to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.
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Acknowledgments |
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This research was supported by National Institutes of Health grant HL-49513 and was performed during Dr Austin’s tenure as an Established Investigator of the American Heart Association.
Received November 3, 1999; revision received January 12, 2000; accepted January 25, 2000.
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 W.-D. Li, C. Dong, D. Li, C. Garrigan, and R. A. Price A genome scan for serum triglyceride in obese nuclear families J. Lipid Res., March 1, 2005; 46(3): 432 - 438. [Abstract] [Full Text] [PDF]
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 J. D. Brunzell Increased ApoB in Small Dense LDL Particles Predicts Premature Coronary Artery Disease Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 474 - 475. [Full Text] [PDF]
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F. Morello, T. W.A. de Bruin, J. I. Rotter, R. E. Pratt, C. J.H. van der Kallen, G. A. Hladik, V. J. Dzau, C.-C. Liew, and Y.-D. I. Chen Differential Gene Expression of Blood-Derived Cell Lines in Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2149 - 2154. [Abstract] [Full Text] [PDF]
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M. C. Carr and J. D. Brunzell Abdominal Obesity and Dyslipidemia in the Metabolic Syndrome: Importance of Type 2 Diabetes and Familial Combined Hyperlipidemia in Coronary Artery Disease Risk J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2601 - 2607. [Abstract] [Full Text] [PDF]
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 T.B. Twickler, G.M. Dallinga-Thie, J.S. Cohn, and M.J. Chapman Elevated Remnant-Like Particle Cholesterol Concentration: A Characteristic Feature of the Atherogenic Lipoprotein Phenotype Circulation, April 27, 2004; 109(16): 1918 - 1925. [Full Text] [PDF]
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 C.C. Shoulders, E.L. Jones, and R.P. Naoumova Genetics of familial combined hyperlipidemia and risk of coronary heart disease Hum. Mol. Genet., April 1, 2004; 13(90001): R149 - 160. [Abstract] [Full Text] [PDF]
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T. Hirano, Y. Ito, S. Koba, M. Toyoda, A. Ikejiri, H. Saegusa, J.-i. Yamazaki, and G. Yoshino Clinical Significance of Small Dense Low-Density Lipoprotein Cholesterol Levels Determined by the Simple Precipitation Method Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 558 - 563. [Abstract] [Full Text]
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M. A. Austin, K. L. Edwards, S. A. Monks, K. M. Koprowicz, J. D. Brunzell, A. G. Motulsky, M. C. Mahaney, and J. E. Hixson Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia J. Lipid Res., November 1, 2003; 44(11): 2161 - 2168. [Abstract] [Full Text] [PDF]
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C. Verseyden, S. Meijssen, H. van Dijk, H. Jansen, and M. C. Cabezas Effects of atorvastatin on fasting and postprandial complement component 3 response in familial combined hyperlipidemia J. Lipid Res., November 1, 2003; 44(11): 2100 - 2108. [Abstract] [Full Text] [PDF]
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P. N. Hopkins, G. Heiss, R. C. Ellison, M. A. Province, J. S. Pankow, J. H. Eckfeldt, and S. C. Hunt Coronary Artery Disease Risk in Familial Combined Hyperlipidemia and Familial Hypertriglyceridemia: A Case-Control Comparison From the National Heart, Lung, and Blood Institute Family Heart Study Circulation, August 5, 2003; 108(5): 519 - 523. [Abstract] [Full Text] [PDF]
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A. F. Ayyobi, S. H. McGladdery, M. J. McNeely, M. A. Austin, A. G. Motulsky, and J. D. Brunzell Small, Dense LDL and Elevated Apolipoprotein B Are the Common Characteristics for the Three Major Lipid Phenotypes of Familial Combined Hyperlipidemia Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1289 - 1294. [Abstract] [Full Text] [PDF]
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R. A. Kreisberg and A. Oberman Medical Management of Hyperlipidemia/Dyslipidemia J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2445 - 2461. [Full Text] [PDF]
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References Circulation, December 17, 2002; 106(25): 3373 - 3421. [Full Text]
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