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(Circulation. 2003;108:519.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

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

Paul N. Hopkins, MD, MSPH; Gerardo Heiss, MD, PhD; R. Curtis Ellison, MD; Michael A. Province, PhD; James S. Pankow, PhD; John H. Eckfeldt, MD, PhD; Steven C. Hunt, PhD

From Cardiovascular Genetics Research, University of Utah, Salt Lake City, UT (P.N.H., S.C.H.); Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC (G.H.); Boston University School of Medicine, Boston, MA (R.C.E.); Division of Biostatistics, Washington University, St Louis, Mo (M.A.P.); Division of Epidemiology, School of Public Health (J.S.P.), and Department of Laboratory Medicine and Pathology (J.H.E.), University of Minnesota, Minneapolis, Minn.

Correspondence to Paul N. Hopkins, MD, MSPH, Cardiovascular Genetics, 410 Chipeta Way, Room 167, Salt Lake City, UT 84108. E-mail paul{at}ucvg.med.utah.edu

Received December 17, 2002; de novo received March 3, 2003; revision received May 9, 2003; accepted May 12, 2003.

	Abstract

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Background— Conventional wisdom suggests that a diagnosis of familial combined hyperlipidemia (FCHL) carries a substantially greater risk of premature coronary artery disease (CAD) than a diagnosis of familial hypertriglyceridemia (FHTG). However, no population-based studies have critically addressed this issue.

Methods and Results— FCHL and FHTG were diagnosed in 10.2% and 12.3% of 334 random control families and in 16.7% and 20.5% of 293 families with at least one case of premature CAD. The diagnosis of either FCHL or FHTG in an individual was associated with an odds ratio for CAD of 2.0 (P=0.003 and 0.002, respectively). However, odds ratios for premature CAD associated with both lipid disorders decreased substantially and identically with further adjustment for hypertension, diabetes, and especially HDL cholesterol, triglycerides, or apolipoprotein B. Similar results were found for differences in carotid intima-medial thickness and ankle-brachial index. Metabolic syndrome was identified in 65% of FCHL and 71% of FHTG patients compared with 19% in controls without FCHL or FHTG and was associated with an odds ratio of 3.3 (P<0.0001). The increased prevalence of the metabolic syndrome alone could account for the elevated CAD risk associated with both FCHL and FHTG.

Conclusions— FCHL and FHTG appear more alike than dissimilar. Further, the risk of CAD in FCHL and FHTG was strongly related to features of the metabolic syndrome. These findings suggest that the hypertriglyceridemia in FHTG is not benign and may warrant a change in epidemiological, genetic, and clinical approaches to these lipid disorders.

Key Words: coronary disease • genetics • lipoproteins • epidemiology

	Introduction

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Conventional wisdom suggests that patients diagnosed with familial combined hyperlipidemia (FCHL) are at greater risk for coronary artery disease (CAD) than patients with familial hypertriglyceridemia (FHTG) and that these are distinct, separate syndromes. Clinicians frequently, therefore, consider hypertriglyceridemia in FHTG as benign but associated with substantial risk in FCHL. This perception appears to be based primarily on a single cross-sectional analysis of premature myocardial infarction history among families identified from lipid clinic patients.¹

Recently, Austin et al² conducted a prospective follow-up of CAD mortality in these same FCHL and FHTG families included together with FCHL and FHTG families ascertained from the seminal studies of Goldstein et al.³ Relative risks for total cardiovascular death (comparing siblings and offspring of probands versus spouse controls) were similar for FCHL and FHTG (odds ratio 1.7 for both, although the risk for FHTG was nonsignificant, presumably due to fewer cases). Interestingly, however, an increase in plasma triglycerides was associated with greater cardiovascular risk in the FHTG families compared with risk in FCHL families.

Surveys among patients selected for premature CAD have identified FCHL and FHTG as among the most common of familial lipid disorders with prevalences reported from 11% to 14% for FCHL and 5.2% to 15% for FHTG.^3,4 Nevertheless, without concomitant assessment of the prevalence of FCHL and FHTG in a control population, no direct estimates of risk are possible from such surveys. Indeed, to date there have been no population-based studies providing either the prevalence of these two common lipid disorders in the general population or the associated coronary risk. The population-based NHLBI Family Heart Study provides an opportunity to address both these questions and to examine factors associated with individual coronary risk.

	Methods

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The NHLBI Family Heart Study was a multicenter, population-based study designed to identify and evaluate genetic and nongenetic determinants of CAD, preclinical atherosclerosis, and cardiovascular disease risk factors.⁵ After written informed consent was obtained, a total of 5381 subjects from 1245 families (588 general population families selected at random and 657 high CAD risk families) completed an extensive clinical examination.^5,6 Blood was obtained after an overnight fast and a single plasma lipid determination was made with LDL calculated from the Friedewald equation⁷ for triglycerides under 400 and by ß-quantification using ultracentrifugation for higher plasma triglycerides.

For purposes of this study, only parents, siblings, or offspring of Family Heart Study probands were considered. Premature CAD cases were defined as males with self-reported myocardial infarction, angioplasty, or coronary bypass surgery by age 55 or females with such events by age 65. These premature CAD cases were ascertained from both randomly selected families from the general population (22.6% of male and 24.8% of female cases) and a group of high-risk families (77.4% of male and 75.2% of female cases). The ages of the cases ranged from 34 to 89 years at the time of examination. Examined relatives of premature CAD cases constituted case families. Hospital records were sought for all 333 CAD cases and obtained to confirm diagnosis in 282; CAD was confirmed in 94.7%. Controls were exclusively derived from the random sample with the same age range (34 to 89 years) as cases; neither they nor any of their family members reported CAD at any age.

To define FCHL and FHTG, all subjects were classified into the following categories: (1) type 2a (90th percentile LDL cholesterol and <90th percentile triglycerides), (2) type 2b (90th percentile LDL cholesterol and 90th percentile triglycerides), (3) type 4 (<90th percentile LDL cholesterol and 90 percentile triglycerides), and (4) unaffected (<90th percentile for both LDL cholesterol and triglycerides). Age- and gender-specific percentile cut points from the Lipid Research Clinics Prevalence Study were used.⁸ A family was classified as having FCHL if at least 2 first-degree relatives in the family were type 2b, or if 2 first-degree relatives had at least 2 different FCHL phenotypes (types 2a, 2b, or 4). FHTG families had two or more first-degree relatives with type 4 without any cases of type 2a or 2b. Subjects taking lipid-lowering medications at the time of the blood draw could have LDL cholesterol above the 50th percentile (representing an approximate 25% reduction in LDL cholesterol) and still be considered to have type 2a or 2b. Of the 133 subjects designated with FCHL, 8 reported that they were currently on lipid-lowering medications. None of the 147 FHTG subjects reported taking lipid-lowering medications. One family with two or more LDL cholesterol levels suggestive of familial hypercholesterolemia based on previously published criteria (LDL 260 mg/dL in one and at least 206 mg/dL in another)⁹ was excluded from consideration of a diagnosis of FCHL or FHTG.

All analyses were performed with SAS version 8.2 for the PC (SAS Institute Inc). Significance of univariate odds ratios were determined by the chi-square test. Odds ratios adjusted for other risk factors were determined using multiple logistic regression as implemented in PROC LOGISTIC. Analysis of variance as implemented in PROC GLM was used to compare means in three groups for continuous variables. Adjustment of hypertension and diabetes prevalences for BMI and other variables was performed with PROC GENMOD using a logistic link function and binary distribution. Potential effects of subject relatedness were tested using PROC GENMOD. As no material differences were noted, probability values obtained with PROC LOGISTIC and PROC GLM are reported.

	Results

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Individual cases of premature CAD included 212 men and 121 women from 293 case families. Individual controls were 774 men and 969 women from 334 control families. Features of the families are shown in Table 1. Both FCHL (univariate OR 1.77, P=0.016, 95% CI 1.11 to 2.83) and FHTG (univariate OR 1.84, P=0.005, 95% CI 1.19 to 2.84) were more common among case families (each family treated as a single observation). Among families with FCHL, the distribution of phenotypes (2a=30.1%, 2b=12.8%, 4=57.1%) was not significantly different comparing case and control families.

View this table: [in this window] [in a new window]   TABLE 1. Features of CAD Case Families and Control Families

Individual risk factors in the 333 premature CAD cases and 1743 controls are shown in Table 2. A total of 33 premature CAD cases were diagnosed with FCHL (9.91%) compared with 100 (5.74%) among controls with a univariate odds ratio of 1.81 (P=0.0044, 95% CI 1.20 to 2.73). Estimated premature CAD risk associated with FHTG was virtually identical, with 36 premature CAD cases (10.81%) and 111 controls (6.37%) being diagnosed with FHTG (OR=1.78, P=0.0038, 95% CI 1.20 to 2.65). Age of onset of CAD was not different comparing FCHL and FHTG CAD cases.

View this table: [in this window] [in a new window]   TABLE 2. Comparison of Risk Factors in Individual Premature CAD Cases and Random Controls

In a further examination of individual risk, the diagnoses of FCHL or FHTG were entered initially into a multiple logistic regression equation with age and gender as the only other independent variables. Additional risk factors were added sequentially in separate models. Results are shown in Table 3. With only age and gender or with age, gender, and cigarette smoking, both FCHL and FHTG were significantly associated with premature CAD with remarkably similar estimated risks. Including other risk factors progressively reduced risk until both became entirely nonsignificant. Surprisingly, entering LDL cholesterol into the model did not affect associated risks for either FCHL or FHTG. In contrast, entering apolipoprotein B (apoB) or particularly triglycerides (as the log) completely eliminated risk for both FCHL and FHTG, suggesting that CAD risk associated with FCHL was as dependent on triglyceride levels as FHTG in this population. Triglycerides remained significant at P0.0001 even when HDL, hypertension, and diabetes were included in the model.

View this table: [in this window] [in a new window]   TABLE 3. Results of Multiple Logistic Regression for Premature CAD (333 Cases and 1743 Controls) Using Individual Diagnosis of FCHL and FHTG as Covariates

The remarkably similar risks of premature CAD associated with FCHL and FHTG in these analyses suggested that these entities were more alike than expected. Furthermore, CAD risks for both appeared to be attenuated similarly by diabetes, hypertension, low HDL cholesterol, and triglycerides—all major components of the metabolic syndrome. Accordingly, all individuals diagnosed with FCHL or FHTG (whether premature CAD cases, other members of case families, or members of control families) were compared with each other for a variety of components of the metabolic syndrome (Table 4). Controls without FCHL or FHTG served as a third comparison group. For virtually all components tested (other than the lipids that comprised the respective definitions), FCHL and FHTG were remarkably similar to each other and significantly different than the controls without FCHL or FHTG. This was also true for carotid artery intima-media thickness (IMT).

View this table: [in this window] [in a new window]   TABLE 4. Elements of the Metabolic Syndrome, Common Carotid IMT (CC IMT), and Ankle-Brachial Index (ABI) in All Subjects (With or Without CAD) Having FCHL or FHTG, and in Random Controls Without FCHL or FHTG

Remarkably, 64.7% of all FCHL and 70.7% of all FHTG patients met the criteria for metabolic syndrome by the guidelines of the National Cholesterol Education Program¹⁰ (P=0.21 comparing FCHL and FHTG). Even higher percentages of premature CAD cases with FCHL or FHTG had metabolic syndrome (76% and 81%, respectively). This compares with only 18.8% of controls with neither FCHL nor FHTG (P<0.0001 for comparisons with both FCHL and FHTG). A diagnosis of metabolic syndrome (without regard to FCHL or FHTG) was associated with a univariate odds ratio for premature CAD of 3.28 (95% CI 2.5801 to 4.1791; P<0.0001) in this population. Risks associated with FCHL and FHTG in logistic regression were eliminated when a diagnosis of metabolic syndrome was included in the model.

After correction for only hypertension, diabetes, and HDL cholesterol, carotid IMT differences between FCHL, FHTG, and controls were reduced and became nonsignificant (adjusted least-square mean±SEM were 0.679±0.018, 0.648±0.016, and 0.652±0.005 for FCHL, FHTG, and controls, respectively; P>0.1 for all comparisons). Similarly, the ankle-brachial index difference between persons with FCHL and controls without FCHL or FHTG became nonsignificant after adjustment for hypertension, diabetes, and HDL cholesterol. This index was most strongly related to cigarette smoking and hypertension (data not shown).

To determine whether differences in body weight, fat distribution, or smoking could account for the differences in expression of various elements of the metabolic syndrome in FCHL and FHTG, we repeated the analyses shown in Table 4 after adjusting for age, gender, cigarette smoking, BMI, and waist circumference. Significant differences persisted for virtually all variables except carotid IMT, which became nonsignificant for FHTG.

	Discussion

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Contrary to the expectation of greater risk for FCHL as compared with FHTG, we found virtually identical risks of premature CAD associated with these two common lipid disorders. Increased CAD risk in FCHL is frequently attributed to elevated production of VLDL and/or LDL. The lack of CAD risk associated with LDL cholesterol in our study and the strong and equal dependencies on triglycerides, apoB, HDL cholesterol, hypertension, and diabetes are therefore even more remarkable. Furthermore, both conditions were equally associated with virtually all elements of the metabolic syndrome. The finding of increased carotid IMT and ankle-brachial index in FCHL and FHTG patients that became nonsignificant after correction for HDL cholesterol, hypertension, and diabetes further suggests that atherosclerosis risk associated with FCHL and FHTG is transmitted primarily together with these major components of the metabolic syndrome.

Our estimates of premature CAD risk associated with FCHL and FHTG appear lower than might have been expected based on the original cross-sectional, largely descriptive Seattle studies of MI survivors¹¹ and families of lipid clinic patients.¹ However, our risk estimates are nearly identical to results based on prospective follow-up of these same families in which only a modest 70% increase in risk was observed.² In the Seattle studies, the proband had to have total cholesterol or triglyceride levels above the 92.5th percentile, whereas for other relatives, a 95th percentile cutoff was used. In addition, at least one relative was required to have a 99th percentile lipid abnormality, leading to inclusion of some families with very high serum cholesterol levels.¹ If some of these families had familial hypercholesterolemia with mixed phenotypes, as may be seen in some cases,^12–14 higher coronary risks might be expected. We elected in the present study to use 90th percentile cut points and to exclude a single family with members having LDL levels suggestive of familial hypercholesterolemia. This approach has become the most commonly utilized definition of FCHL.^15–19

The prevalence of FCHL (5.7%) that we found among individuals in our randomly ascertained population is considerably higher than the 0.5% to 2% estimates for FCHL from some studies using 95th percentile lipid cutoffs.^3,20 When we used 95th percentile total cholesterol and triglyceride cutoffs and required at least two different phenotypes, we found prevalences of FCHL of 4.50% and 3.27% in our cases and controls, respectively (OR for CAD 1.40, 95% CI 0.78 to 2.50; P=0.26). FHTG prevalences were 5.41% and 1.49%, respectively (OR for CAD 3.77, 95% CI 2.04 to 6.96; P<0.0001). Furthermore, when we defined FHTG using 95th percentile cutoffs, further correction for hypertension, diabetes, or HDL diminished but did not remove the risk associated with FHTG (data not shown), whereas FCHL remained nonsignificant. These findings further strengthen our observation that the elevated triglycerides in FHTG are not benign.

In contrast to the unexpectedly high rates of FCHL and FHTG in our randomly ascertained, general population, the prevalences of these lipid disorders among our premature coronary cases were similar to other series.^3,4 Thus, the relatively low odds ratios for premature CAD risk associated with FCHL and FHTG in our study are primarily due to unexpectedly high prevalence of these lipid disorders in the CAD-free, control population.

FCHL is metabolically heterogeneous. Whereas overproduction of VLDL, with or without overproduction of LDL, appears to be the most common kinetic mechanism in FCHL probands,²¹ at least one FCHL family has been clearly documented with impaired removal of both VLDL and LDL.²² The few investigations comparing kinetics in families with FCHL and FHTG found increased VLDL production most commonly in both with few kinetic differences.^23,24 Whereas impaired processing of VLDL makes heterozygous lipoprotein lipase deficiency an obvious candidate for FHTG,²⁵ some families with FCHL appear to have this abnormality and may even show overproduction of VLDL as a result.^26,27 Thus, from studies to date, kinetic mechanisms do not clearly distinguish FCHL from FHTG.

Our findings that a large percent of both FCHL and FHTG subjects also met diagnostic criteria for metabolic syndrome, and that CAD risk for both (using 90th percentile LDL and triglyceride cutoffs) was eliminated when metabolic syndrome was included in logistic models, suggests one or more shared etiological features such as increased intraabdominal fat.^28,29 The persistence of differences between controls and FCHL or FHTG in our study and by others¹⁷ after adjustment for BMI and waist circumference is consistent with additional etiological factors.

In conclusion, FCHL and FHTG appear to be more alike than distinct in their prevalence, their metabolic profile, associated risk factors, and associated risk of premature CAD. Clinically, identification and treatment of metabolic syndrome (including all lipid abnormalities) may yield greater benefits than rigorous differential diagnosis of FCHL or FHTG because most of the associated coronary risk appears to be subsumed by features of the metabolic syndrome. These findings may warrant a change in epidemiological, genetic, and clinical approaches to FCHL and FHTG, recognizing that elevations of plasma triglycerides are not benign even when high LDL is not found in the family.

	Acknowledgments

 
Support for this work was provided by NHLBI grants U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568, and U01 HL56569.

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