Molecular diagnosis of familial hypercholesterolaemia in the diverse South African population

English: Coronary heart disease (CHD) is one of the leading causes of mortality in Westernised countries and accounts for approximately 25% of all deaths. Elevated lipid and lipoprotein levels leading to atherosclerosis, affects about 4.8 million South Africans, placing them at high risk for developing CHD. Familial hypercholesterolaemia (FH) and familial defective apolipoprotein B-100 (FDB) are autosomal co-dominant inherited lipid disorders, the hallmark of these phenotypes being the elevation of plasma cholesterol concentrations and premature mortality from cardiovascular complications. Molecular defects in the low density lipoprotein receptor (LDLR) gene and apolipoprotein B (APOB) gene, respectively, underlie the phenotype in FH and FDB. DNA analysis of these loci, using a combination of three mutation screening strategies, was performed in the diverse South African population. No FDB-causing mutation was detected in any of the clinically defined hypercholesterolaemic patients included in the study, which underlines the low prevalence of this lipid disorder in the South African population. A high sensitivity of extensive combined mutation screening strategies was demonstrated, since molecular lesions were detected in all Jewish hypercholesterolaemic patients analysed. Despite this, the gene defects could not be identified in all the clinically defined Afrikaner FH patients analysed. The disease phenotype in these patients may be caused by mutations in other genes underlying autosomal dominant hypercholesterolaemia (ADH). The high prevalence of FH in several of the genetically distinct populations of South Africa, particularly the Afrikaners and Jews (-1/70), allows a population-based screening strategy. In addition to the three previously described Afrikaner founder mutations (0154N, 0206E and V408M), two possibly minor founder mutations, D200G and S258L, were detected in Afrikaner FH homozygotes. Inclusion of these LDLR gene defects in routine DNA screening would improve the diagnostic service for FH. The Jewish founder mutation, 652de1GGT, predominates in the majority (57%) of South African Jewish patients screened. This mutant allele became more prevalent in FH Jews of Lithuanian lineage (75%). LDLR gene mutation, N407K, identified in an Afrikaner-Jewish FH patient who is also heterozygous for mutation, 0206E, appears to be associated with a mild FH phenotype. Follow-up family studies demonstrated that genotype-phenotype correlation studies are of utmost importance for the implementation of preventive treatment strategies. Gender, age, race, home language, historical affiliation with specific religious groups, geographical distribution, as well as specific disease phenotypes may impart to the heterogeneous distribution of mutant alleles in a homogeneous population. The distribution of the three founder-related Afrikaner LDLR gene defects was shown to correlate significantly with home language (Afrikaans or English) and historical membership with the Gereformeerde Church. Analysis of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in the Afrikaner population supports the notion that age and the genetic background of population subgroups may contribute to the heterogeneity of this genetic marker. The potential for different degrees of linkage disequilibrium of the ACE I/D polymorphism with other potentially significant sequence changes in the gene and the modest degree of increased risk for CHD associated with the ACE DD genotype, argued against the likelihood of this marker being a clinically useful indicator of increased risk for CHD in Afrikaner FH patients. This study highlights the potential prognostic value of DNA diagnosis in populations where a small number of mutations cause the disease in the vast majority of affected cases. The possible role of modifier genes in the phenotypic expression of FH has to be considered within a specific population context, since gene-environment interaction most likely contributed to the unique genetic make-up of the diverse South African population. A comprehensive multilocus risk assessment strategy, including complete genotyping and accurate interpretation of genetic data, should in future be applied to determine an individual's risk for the development of CHO. Molecular analysis of patients with the FH phenotype may be considered a prerequisite for accurate diagnosis, genetic counselling and optimal treatment targeted at the cause of the disease.