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Title: Reverse genetics of familial combined hyperlipidaemia
Author: Worsley, Andrew Peter
ISNI:       0000 0001 3572 789X
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1993
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Familial combined hyperlipidaemia (FCHL) is a common inherited disorder of lipid metabolism, with a prevalence of 0.5%-2% in Caucasians. It was first described in 1973 by Goldstein et al. and is characterised by raised plasma cholesterol and triglyceride levels and by small dense low density lipoprotein (LDL) particles. The principal strategy to identify the underlying defects in FCHL in this study was that of reverse genetics. A total of 43 pedigrees where the proband had combined hyperlipidaemia were assembled. Thirteen of these pedigrees were defined as having FCHL according to the criteria of Goldstein et al, and by small dense LDL. Population association was performed using twelve of these, ascertained without prior knowledge of their genotype. Linkage analysis was performed in all thirteen pedigrees. Population association demonstrated linkage disequilibrium between FCHL and the 6.6 kilobase (X2) allele of the XmnI RFLP in the apo AI-CIII-AIV cluster (p< 0.021). Linkage analysis was carried out in seven FCHL families in which the proband carried this X2 allele. The peak lod score was 5.87 at 0 = 0.00, demonstrating that FCHL was linked to the apo AI-CIII-AIV locus in this pedigree subset. Furthermore, apo CIII levels in this subset were significantly elevated in affected members (p < 0.0001), suggesting that the defect is associated with increased levels of apo CIII. Subsequent analysis in the six FCHL pedigrees in which the proband did not carry the X2 allele demonstrated a negative lod score of -5.67, indicating that a major subset of FCHL pedigrees are not linked to the apo AI-CIII-AIV locus, and suggesting that FCHL is genetically heterogeneous. The admixture test at this locus using the lod scores from all thirteen pedigrees verified the presence of genetic heterogeneity (p< 0.001), and indicated linkage in the subset of pedigrees carrying the X2 allele (p< 0.0001). These results demonstrate that combined hyperlipidaemia in the X2 FCHL pedigree subset is caused by a defect in or close to the apo AI-CIII-AIV locus on chromosome 11q23-q24. In the remaining pedigrees, FCHL is linked to one or more further gene loci. At 8 further candidate loci, linkage analysis failed to detect other major genes for FCHL. However, the detection of a mutation in the lipoprotein lipase gene in a single additional FCHL pedigree indicates that defects in this gene may also cause FCHL, and further confirms genetic heterogeneity in this disorder. The principal findings of this study suggest that FCHL is genetically heterogeneous and is caused by a defect in at least two major gene loci. These are predominantly the apo AI-CIII-AIV cluster (or a nearby gene) and the lipoprotein lipase gene.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Lipid metabolism; Cholesterol; Cardiovascular