Doctoral Degrees (General Medicine)

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    Comparative analysis of familial hypercholestrerolaemia in different populations
    (Stellenbosch : Stellenbosch University, 1999-12) Thiart, Rochelle; Kotze, Maritha J.; De Jong, G.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine.
    ENGLISH SUMMARY: Familial hypercholesterolaemia (FH) and familial defective apolipoprotein B-IOO (FDB) are relatively common disorders of lipid and lipoprotein metabolism caused by mutations in the low density lipoprotein receptor (LDLR) and apolipoprotein B (apo B) genes, respectively. DNA analyses at these loci were performed in 132 molecularlyuncharacterised South African, 11 Costa Rican and 13 New Zealand subjects with clinical features of heterozygous FH. Mutation R3500Q causing FDB was identified in a relatively large proportion (~30%) of the New Zealand patients. LDLR gene defects were identified in 4 Costa Rican and 6 New Zealand FH patients. Sixty-five different LDLR gene mutations were identified in South African hypercholesterolaemics, revealing ten founder-type mutations. Haplotype analysis at the LDLR and apo B loci excluded the likelihood that mutations in these two genes underlie the FH phenotype in one of the New Zealand families. The apparently autosomal dominant hypercholesterolaemia (ADH) in this family could also not be linked to a newly identified gene locus, designated FH3. Analysis of the New Zealand study cohort, although small, demonstrated both mutational and locus heterogeneity in ADH. Analysis was also extended to include subjects from the various ethnic groups within South Africa. The high prevalence of FH in Afrikaners of European descent is in striking contrast to the reported virtual absence of this lipid disorder in the Black South African population. In addition to three previously-described Afrikaner founder mutations (D154N, D206E and V408M), four minor founder mutations, D200G, S285L, C356Y and G361V, were identified in 12 Afrikaner families. Surprisingly, a 6-bp deletion in exon 2 of the LDLR gene was detected at a relatively high frequency (28%) in Black FH patients. This finding, as well as clinical correlations performed in the patients, suggests that the expression of FH mutations in the Black population may be altered due to interaction with other genetic and/or environmental factors, therefore leading to underdiagnosis of the disease. Common LDLR gene mutations have also been described in South African Indians (P664L) and Jews (del 197), most likely as a consequence of multiple introductions of defective genes into these relatively isolated communities. Caucasoid admixture was recognised as a major factor contributing to the FH phenotype in the indigenous South African population of mixed ancestry from the Western Cape, where six founder-type mutations account for the disease in 22% of cases. The high prevalence of specific LDLR gene mutations in different population groups facilitates an improved diagnostic service for FH in South Africa.