Comparative analysis of familial hypercholestrerolaemia in different populations

[摘要] ENGLISH SUMMARY: Familial hypercholesterolaemia (FH) and familial defective apolipoprotein B-IOO (FDB)are relatively common disorders of lipid and lipoprotein metabolism caused by mutationsin the low density lipoprotein receptor (LDLR) and apolipoprotein B (apo B) genes,respectively. DNA analyses at these loci were performed in 132 molecularlyuncharacterisedSouth African, 11 Costa Rican and 13 New Zealand subjects withclinical features of heterozygous FH. Mutation R3500Q causing FDB was identified in arelatively large proportion (~30%) of the New Zealand patients. LDLR gene defectswere identified in 4 Costa Rican and 6 New Zealand FH patients. Sixty-five differentLDLR 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 thatmutations in these two genes underlie the FH phenotype in one of the New Zealandfamilies. The apparently autosomal dominant hypercholesterolaemia (ADH) in thisfamily could also not be linked to a newly identified gene locus, designated FH3.Analysis of the New Zealand study cohort, although small, demonstrated both mutationaland locus heterogeneity in ADH.Analysis was also extended to include subjects from the various ethnic groupswithin South Africa. The high prevalence of FH in Afrikaners of European descent is instriking contrast to the reported virtual absence of this lipid disorder in the Black SouthAfrican population. In addition to three previously-described Afrikaner foundermutations (D154N, D206E and V408M), four minor founder mutations, D200G, S285L, C356Y and G361V, were identified in 12 Afrikaner families. Surprisingly, a 6-bpdeletion in exon 2 of the LDLR gene was detected at a relatively high frequency (28%) inBlack 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 dueto interaction with other genetic and/or environmental factors, therefore leading tounderdiagnosis of the disease. Common LDLR gene mutations have also been describedin South African Indians (P664L) and Jews (del 197), most likely as a consequence ofmultiple introductions of defective genes into these relatively isolated communities.Caucasoid admixture was recognised as a major factor contributing to the FH phenotypein 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 highprevalence of specific LDLR gene mutations in different population groups facilitates animproved diagnostic service for FH in South Africa.

[发布机构] Stellenbosch University