Genetic predictors of FCHL in four large pedigrees. Influence of ApoB level major locus predicted genotype and LDL subclass phenotype.

Abstract

The genetic basis of familial combined hyperlipidemia (FCHL) has eluded investigators for 20 years, despite the apparent segregation of FCHL as an autosomal dominant disorder affecting 1% to 2% of individuals. Etiologic heterogeneity and additive effects of traits controlled by other genetic loci have been suggested. Two traits have been implicated in FCHL. The first is the predominance of a small, dense low-density lipoprotein (LDL), LDL subclass phenotype B, which segregates as a mendelian trait. The second is a mendelian locus with large effects on apolipoprotein (apo) B levels that is defined by complex segregation analysis (predicted apoB level genotype). This study shows that these factors F amilial combined hyperlipidemia (FCHL) is characterized by variable expression of hypercholesterolemia and hypertriglyceridemia in a given family, with either or both present in affected individuals.1 FCHL is associated with an excess risk of coronary artery disease (CAD) and was first reported by Goldstein et al 1 in 1973 in pedigrees ascertained through men who were survivors of myocardial infarction; over 10% of those probands were considered to have FCHL. One half to one third of familial premature CAD 2 and at least 10% of all premature CAD 1 -3 are ascribed to FCHL. This disorder is estimated to affect 1% to 2% of those in the populations studied and may be responsible for 5% of myocardial infarctions.1 While the inheritance of FCHL was originally described as consistent with an autosomal dominant disorder with full penetrance by the end of the third decade, 1 formal segregation analysis, adjusting for ascertainment, has not been reported. 4 Thus, the mode of inheritance remains uncertain.Efforts to refine the phenotype of FCHL have led to the observation that elevated levels of apolipoprotein Received May 4, 1994; revision accepted July 19, 1994. O 1994 American Heart Association, Inc.appear to be separate genetic effects, both of which aid in the prediction of FCHL in four large pedigrees. The results suggest that FCHL may be best predicted by a threshold model in which apoB level genotype and LDL subclass phenotype each act to increase the risk of FCHL. Heterogeneity in the transmission of apoB levels among families is suggested, supporting the etiologic heterogeneity of FCHL. These results emphasize the advantages inherent in the study of large pedigrees when disease heterogeneity is suspected.

Impaired Insulin-Stimulated Glucose Oxidation and Free Fatty Acid Suppression in Patients with Familial Combined Hyperlipidemia

“…First, insulin resistance may be independent of dyslipidemia in FCHL families, implying that insulin resistance and dyslipidemia have different etiologies in this disease. Secondly, in addition to insulin resistance, some other defect may be needed for dyslipidemia to develop (additive effect for example with the apoB locus 32 ). Finally, insulin resistance may be an inherited characteristic of FCHL and precede dyslipidemia.…”

Quantitative Trait Loci for Apolipoprotein B, Cholesterol, and Triglycerides in Familial Combined Hyperlipidemia Pedigrees

“…As with most genetically complex disorders, the binary classification of family members into affected and unaffected may not be the best phenotype for finding disease-predisposing genes, because such classifications do not follow a classical Mendelian pattern of inheritance. [5][6][7] These increased lipid levels are likely to result from the interaction of multiple genes and environmental factors, such as adiposity and the degree of exercise, and the individual quantitative lipid profiles may be closer to the genetic defects than the binary definition of FCHL. In addition, it is anticipated that the wide variance of quantitative traits will provide more statistical power to detect linked loci than the binary categorization of FCHL.…”

Pleiotropic Genetic Effects on LDL Size, Plasma Triglyceride, and HDL Cholesterol in Families

“…Although the specific genetic bases of both FCHL and FHTG are poorly understood, studies indicate major gene effects on TG and apo B in FCHL families. 12,13 In addition, there is also considerable evidence for genetic influences on LDL subclass phenotypes 12,14 -18 and HDL-C. 19 -22 Statistical and physiological relationships between measures of LDL size, plasma TG, and HDL-C are well established 3,[23][24][25] and may represent a high-CHD-risk lipid/ lipoprotein phenotype with common underlying genetic influences. Sprecher et al 26,27 first proposed that the combination of high TG and low HDL-C constituted an inherited "conjoint trait" associated with increased risk of CHD in families of hypertriglyceridemic or hypercholesterolemic probands participating in the Lipid Research Clinics Family Study.…”