Elsevier

Atherosclerosis

Volume 157, Issue 2, August 2001, Pages 481-489
Atherosclerosis

Excess coronary heart disease in Familial Combined Hyperlipidemia, in relation to genetic factors and central obesity

https://doi.org/10.1016/S0021-9150(00)00752-8Get rights and content

Abstract

Aim: To determine the prevalence of non-fatal coronary artery disease (CAD) in kindred with Familial Combined Hyperlipidemia (FCHL) in relation to various cardiovascular risk factors and DNA variation in the apo AI-CIII-AIV gene cluster. Methods and Results: Data were collected from 18 Dutch FCHL probands, 202 living first and second degree relatives, and 175 spouses. Probands and first degree relatives showed dyslipidemia, increased plasma insulin and glucose concentrations, higher waist–hip ratio (WHR), and blood pressure, than spouses. The frequency of the minor alleles M2 and S2 was increased in probands and first degree relatives. The Odds Ratio for CAD was 5.3 in male FCHL relatives (P=0.005), and 5.1 in all FCHL relatives (P=0.001). First and second degree relatives had a markedly reduced CAD-free life-span (log rank vs. spouses: P<0.001 and P=0.03, respectively). The presence of the S2, but not M2, minor allele, showed a marked reduction in CAD-free life-span (logrank S2 present vs. S2 absent: P=0.035). Conclusion: Men with FCHL have a severely increased risk of CAD, that appears to be mediated through genetic relation to the proband as the strongest independent risk factor for CAD, followed by increased WHR.

Introduction

Familial combined hyperlipidemia (FCHL) is one of the most common genetic lipid disorders [1], [2], [3], [4] affecting approximately 10% of the survivors of myocardial infarction (MI) [2], [4], [5], whereas the population frequency is estimated at 1:200 or 0.5% [2], [4], [6]. FCHL is therefore associated with a substantially increased risk of coronary artery disease (CAD).

FCHL is characterized by a variable expression of both hypercholesterolemia and hypertriglyceridemia among different affected relatives [2], [7]. FCHL subjects present with increased plasma levels of the apoB containing lipoproteins, including very low density lipoproteins (VLDL) [8], low density lipoproteins (LDL) [9], and small dense LDL particles [10], [11], [12], [13]. Additionally, FCHL subjects are insulin resistant [14], [15]. Clearly, the aggregate of these abnormalities results in an unfavorable, atherogenic risk profile, but identification of a specific abnormality responsible for the increased risk for CAD has not yet been achieved.

FCHL is regarded as a clinical entity [2] caused by a major gene and contributing modifier genes [16], [17]. The apo AI-CIII-AIV gene cluster, located on chromosome 11, has been implied as a possible modifying gene [17], [18], influencing lipid and apolipoprotein profiles in FCHL subjects. Because a single biochemical or genetic marker for FCHL is unavailable at present, family studies are still required for the diagnosis [2], [7], [18], [19], [20].

Quantitative observations on the risk of CAD in FCHL relatives are scarce, although it is known that in FCHL kindred a positive family history for premature CAD is present [1], [2], [3]. A recent publication by Austin et al. [21] showed that the 20-year cardiovascular mortality in FCHL kindred was a factor 1.7 higher than in spouse controls. However, this may represent an underestimation of the true risk, because spouse controls showed a remarkably high cardiovascular mortality of 9.8% and total mortality of 29.4%. Furthermore, no data are yet available on non-fatal CAD risk in FCHL, the risk associated with second degree relatives, and potential gender differences. The objective of the present study was therefore to evaluate the prevalence of manifestations of non-fatal CAD (defined as non-fatal MI, or a history of PTCA and CABG), in relation to lipid abnormalities, clinical measures of insulin resistance and variations in the apo AI-CIII-AIV gene cluster in probands, first and second degree relatives of 18 well characterized FCHL kindred.

Section snippets

FCHL families

Eighteen unrelated Caucasian FCHL index patients (probands) were identified at our Lipid Clinic. The following inclusion criteria were used [17]: (a) a primary combined hyperlipidemia with varying phenotypic expression including fasting plasma cholesterol (Chol)>6.5 mmol/l (250 mg/dl) and/or fasting plasma triglyceride (TG) concentration>2.3 mmol/l (200 mg/dl); (b) at least one first-degree relative with a different hyperlipidemic phenotype from the proband; (c) a positive family history of

Subjects

Seven of the 18 kindred in the study were diagnosed based on CAD in the probands. The remaining 11 kindred were diagnosed as FCHL because CAD was present in a deceased first degree relative, and implicated as the cause of death. The subjects under study included 91 first degree relatives, 111 second degree relatives, and 175 spouses. This represented 95% of all living first and second degree relatives.

Subject characteristics

Clinical and biochemical characteristics of the FCHL probands, relatives and spouses are

Discussion

This study showed that not only FCHL probands, but male first and second degree FCHL relatives as well, exhibit a severely increased risk of non-fatal CAD, compared to spouses. FCHL is therefore characterized as a biologically aggressive genetic disorder of lipid and glucose metabolism. Earlier crude estimates suggest an FCHL-associated risk of MI between 5 and 20 [2], [5]. In the present study, we provide an exact estimate, with an overall Odds Ratio for non-fatal CAD of 5.1 in all FCHL

References (48)

  • R.P. Donahue et al.

    Central obesity and coronary heart disease in men

    Lancet

    (1987)
  • S.M. Haffner et al.

    Hyperinsulinemia, upper body adiposity, and cardiovascular risk factors in non-diabetics

    Metabolism

    (1988)
  • J.L. Goldstein et al.

    Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia

    J. Clin. Invest.

    (1973)
  • J.J. Genest et al.

    Familial lipoprotein disorders in patients with premature coronary artery disease

    Circulation

    (1992)
  • A.G. Motulsky

    Current concepts in genetics; the genetic hyperlipidemias

    N. Engl. J. Med.

    (1976)
  • A. Chait et al.

    Very low density lipoprotein overproduction in genetic forms of hypertriglyceridaemia

    Eur. J. Clin. Invest.

    (1980)
  • A.H. Kissebah et al.

    Low density lipoprotein metabolism in familial combined hyperlipidemia. Mechanism of the multiple lipoprotein phenotypic expression

    Arteriosclerosis

    (1984)
  • M.A. Austin et al.

    Inheritance of low density lipoprotein subclass patterns in familial combined hyperlipidemia

    Arteriosclerosis

    (1990)
  • S.J.H. Bredie et al.

    Inherited susceptibility determines the distribution of dense low-density lipoprotein subfraction profiles in familial combined hyperlipidemia

    Am. J. Hum. Genet.

    (1996)
  • S.J.H. Bredie et al.

    Metabolic and genetic aspects of familial combined hyperlipidaemia with emphasis on low-density lipoprotein heterogeneity

    Eur. J. Clin. Invest.

    (1997)
  • J.E. Hokanson et al.

    LDL physical and chemical properties in familial combined hyperlipidemia

    Arterioscler. Thromb. Vasc. Biol.

    (1995)
  • S.J.H. Bredie et al.

    Nonobese patients with familial combined hyperlipidemia are insulin resistant compared with their nonaffected relatives

    Arterioscler. Thromb. Vasc. Biol.

    (1997)
  • S.C. Hunt et al.

    Apolipoprotein, low density lipoprotein subfraction, and insulin associations with familial combined hyperlipidemia. Study of Utah patients with familial dyslipidemic hypertension

    Arteriosclerosis

    (1989)
  • P. Pajukanta et al.

    Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23

    Nat. Genet.

    (1998)
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