Excess coronary heart disease in Familial Combined Hyperlipidemia, in relation to genetic factors and central obesity
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
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2014, AtherosclerosisCitation Excerpt :Familial Combined Hyperlipidemia (FCH) is the most common genetic dyslipidemia with estimated prevalence approximately 1% in the general population [10]. It is associated with a number of metabolic disorders such as hypertension, obesity, insulin resistance, diabetes and metabolic syndrome and it is an important cause of premature CAD [11,12]. Heterozygous familial hypercholesterolemia (hFH), another common genetic disorder that leads to premature CAD, affects approximately 1 in 500 people in Europe [13].
Carotid atherosclerosis and lipoprotein particle subclasses in familial hypercholesterolaemia and familial combined hyperlipidaemia
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