Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry

Abstract

The South African population harbors genes that are derived from varying degrees of admixture between indigenous groups and immigrants from Europe and the East. This study represents the first direct mutation-based attempt to determine the impact of admixture from other gene pools on the familial hypercholesterolemia (FH) phenotype in the recently founded Coloured population of South Africa, a people of mixed ancestry. A cohort of 236 apparently unrelated patients with clinical features of FH was screened for a common mutation causing familial defective apolipoprotein B-100 (FDB) and seven low-density lipoprotein receptor (LDLR) gene defects known to be relatively common in South Africans with FH. Six founder-type 'South African mutations' were responsible for FH in approximately 20% of the study population, while only 1 patient tested positive for the familial defective apolipoprotein B-100 mutation R3500Q. The detection of multiple founder-type LDLR gene mutations originating from European, Indian and Jewish populations provides direct genetic evidence that Caucasoid admixture contributes significantly to the apparently high prevalence of FH in South African patients of mixed ancestry. This study contributes to our knowledge of the biological history of this unique population and illustrates the potential consequences of recent admixture in populations with different disease risks.

Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia

“…Patients carrying the four mutations that showed low penetrance were included in this analysis, because it is well-known that cases of low penetrance in children are often observed ( 34,35 ), even in families with functional mutations (two out of four are functional mutations). Carriers of three other mutations that showed weak cosegregation were also included, because these alterations were described before as mutations causing disease by experienced groups in the FH fi eld (36)(37)(38)(39)(40)(41)(42)(43). Pathogenicity of the remaining 11% was assessed by segregation analysis of the mutations with the phenotype in those families, amino acid nature and conservation in different species, and absence in the normolipidemic Portuguese control panel [Cotton and Scriver criteria ( 31 )], and therefore have been accepted as pathogenic in the present cohort.…”

The Glu298Asp variant of the endothelial nitric oxide synthase gene is associated with an increased risk for abruptio placentae in pre-eclampsia

“…Informed consent was obtained from all study participants. Patient and control individuals were from the South African ''Coloured'' population group who have San, Khoi, Madagascan, Javanese and European ancestry (Loubser et al 1999). The admixture events occurred multiple generations ago and the Coloured group is an established population in South Africa.…”

Analysis of mutations causing familial hypercholesterolaemia in black South African patients of different ancestr

“…In the 16 black African subjects, eight predicted FH-causing mutations were identified. Several mutations previously reported in black African subjects were seen, [11] and two novel variants were identified. Both novel variants were predicted to be pathogenic by in silico analysis, but while co-segregation studies in the relatives of these patients would be valuable, family members were unavailable for such studies.…”

“…For example, three founder mutations, p.(D227E), p.(V429M) and p.(D175N), account for ~90% of FH cases among the Afrikaners in SA. [11] There is great value in characterising the FH mutation spectrum of a particular population for population screening in order to identify potential patients at risk by genetic cascade testing and reduce cardiovascular morbidity and mortality. For over a decade, there have been no published findings examining the spectrum of mutations causing FH in the black SA population.…”