Confirmed Locus on Chromosome 11p and Candidate Loci on 6q and 8p for the Triglyceride and Cholesterol Traits of Combined Hyperlipidemia

Abstract

Background— Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and triglyceride or either lipid alone) is unknown. Methods and Results— We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities. Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, and 11p14.1-q12.1 produced evidence for linkage to FCHL. Chromosomes 6 and 8 are newly identified candidate loci that may respectively contribute to the triglyceride (logarithm of odds [LOD], 1.43; P =0.005) and cholesterol (LOD, 2.2; P =0.0007) components of this condition. The data for chromosome 11 readily fulfil the guidelines required for a confirmed linkage. The causative alleles may contribute to the inheritance of the cholesterol (LOD, 2.04 at 35.2 cM; P =0.0011) component of FCHL as well as the triglyceride trait (LOD, 2.7 at 48.7 cM; P =0.0002). Conclusions— Genetic analyses identify 2 potentially new loci for FCHL and provide important positional information for cloning the genes within the chromosome 11p14.1-q12.1 interval that contributes to the lipid abnormalities of this highly atherogenic disorder.

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia

“…Both FCHL and type 2 diabetes mellitus provide similar examples in which the second study cohort originating from the same population as the original one fails to show evidence for linkage for some of the identified regions (46,47). It has been suggested that differences in family structures or in the frequency of a disease-causing allele within families could contribute to the power to detect linkage, especially in the case of small study samples (47)(48)(49)(50). Furthermore, additional families and significant extension of existing families probably also pose a risk of introducing increased genetic heterogeneity within and between the families.…”

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

“…13 Although it was not among the strongest results, linkage to this region with Pϭ0.014 has also been reported for cholesterol in an independent cohort of British FCHL families. 12 Because cholesterol-carrying lipoproteins have apoB as their structural apoprotein, and FCHL is characterized by elevated plasma levels of apoB containing VLDL and low-density lipoproteins (LDL), this is not unexpected. The putative gene in this region may have a pleiotropic effect on increased total serum cholesterol and apoB within FCHL pedigrees.…”

“…11 Recently, very promising findings were generated by analyzing the FCHL diagnosis or a related binary trait derived from increases over age/sex-specific cutoff values. These include linkage to 1q in large Finnish pedigrees, followed by successful association analyses of a positional candidate gene, upstream transcription factor 1, 16 replication of a linked region on 11p, 11,12 and a combined analysis of Finnish and Dutch families, which showed linkage to 16q. 17 Although some analyses of the quantitative lipid traits associated with FCHL have been included in these gene finding investigations, they have rarely been the main focus of the studies.…”

The involvement of upstream stimulatory factor 1 in Dutch patients with familial combined hyperlipidemia

“…During the past few years, several groups have performed linkage analyses in an attempt to determine the genetic defects causing FCH (3)(4)(5)(6)(7)(8). By doing this, a locus on chromosome 1q21-23 was identified (4,(7)(8)(9).…”