Comparative analysis of familial hypercholestrerolaemia in different populations

Thiart, Rochelle (1999-12)

Thesis (Ph.D.) -- University of Stellenbosch, 1999.


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.

AFRIKAANSE OPSOMMING: Familiele hipercholesterolemie (FH) en familiele defektiewe apolipoprotelen B-I00 (FDB) is relatief algemene afwykings in lipied en lipoprotelen metabolisme wat onderskeidelik veroorsaak word deur mutasies in die lae digtheids lipoprotelen reseptor (LDLR) en apolipoproteleri B-I00 (apo B) gene. Molekulere DNS analise van hierdie lokusse is uitgevoer in 132 Suid Afrikaanse, 11 Costa Rikaanse en 13 New Zealandse pasiente waar die geen mutasies onderliggend, aan die kliniese beeld van heterosigotiese FH onbekend was. Mutasie R3500Q wat FDB veroorsaak was in 'n relatief groot aantal van die New Zealandse pasiente (~30%) teenwoordig. LDLR geen defekte is in 4 Costa Rikaanse en 6 New Zealandse FH pasiente geldentifiseer. Vyf en sestig verskillende LDLR geen mutasies is aangetoon in die Suid Afrikaanse populasie waarvan tien stigtergeen mutasies is. Haplotipe analise van die LDLR en apo B lokusse het die moontlikheid uitgesluit dat mutasies in hierdie twee gene verantwoordelik is vir die FH fenotipe in een van die New Zealandse families. Die waarskynlik outosomaal dominante hipercholesterolemie (ODH) in hierdie familie kon ook nie toegeskryf word aan 'n nuwe geidentifiseerde geen lokus genaamd FH3 nie. Analise van die New Zealandse studie paneel het dus beide mutasie en lokus heterogeniteit in ODH gedemonstreer. Analise was uitgebrei deur die toevoeging van individue van verskeie etniese groepe van Suid-Afrika. Die hoe voorkoms van FH in Afrikaners van Europese afkoms is , in opvallende kontras met die voorheen vermeende feitlike afwesigheid van hierdie lipied afwyking in die Swart Suid-Afrikaanse populasie. Afgesien van drie bekende Afrikaner stigter mutasies (D154N, D206E en V408M), is nog vier relatief algemene mutasies, D200G, S285L, C356Y en G361V, ge'identifiseer in 12 Afrikaner families. 'n Onverwagse bevinding was die opsporing van 'n 6-bp delesie in ekson 2 van die LDLR geen teen 'n relatief hoe frekwensie (28%) in Swart FH pasiente. Hierdie bevinding, sowel as kliniese korrelasies wat in hierdie groep pasiente uitgevoer is, impliseer dat FH moontlik ondergediagnoseer word in die Swart populasie weens interaksie van defektiewe LDLR gene met ander genetiese en/of omgewingsfaktore. Algemene LDLR geen mutasies is ook beskryf in Suid Afrikaanse Indiers (P664 L) en J ode (del 197), heel waarskynlik as 'n gevolg van veelvuldige oordrag van defektiewe gene in hierdie relatief geisoleerde gemeenskappe. Kaukasier vermenging is herken as 'n belangrike faktor onderliggend aan die FH fenotipe in die inheemse W es-Kaapse kleurling populasie van Suid-Afrika, waar ses stigter-tipe mutasies verantwoordelik is vir die siekte in 22% van' gevalle. Die hoe voorkoms van spesifieke LDLR geen mutasies in verskillende populasie groepe maak populasie-gerigte DNA dililgnose van FH moontlik in Suid Afrika.

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