Genetic polymorphism of apolipoprotein (apo) E has been shown to account for a significant amount of variance in plasma lipid and lipoprotein levels, thereby contributing to the incidence of cardiovascular disease across populations. In this cross-sectional study apo E genotypes were determined in a sample of 173 healthy, middle-aged Indian women using a restriction isotyping method, in which DNA was amplified by PCR and the Cfol restricted DNA fragments were separated on a polyacrylamide gel, allowing unambiguous typing of the common apo E genotypes. Considering the three common alleles, e2, e3 and e4, a reduced frequency of the e2 allele was observed in the study population in comparison to other populations around the world. This finding underlines the heterogeneity of apo E allele frequencies in different populations. This study also investigated possible effects of apo E genotype on lipoprotein changes in this sample of women spanning the menopause. Apo E polymorphism was associated with significant differences in plasma lipid levels. Notably, total and low density lipoprotein cholesterol and more especially plasma triglyceride concentrations were increased in carriers of the e3/4 genotype. Two-way analysis of variance of the effect of apo E genotype and menopausal status on the lipid profile showed no significant interaction effect, indicating that the effects of apo E genotype on the lipid profile do not differ significantly between premenopausal and postmenopausal women. Age and to a lesser extent the waist hip ratio also correlated with lipid concentrations, but menopausal status had no apparent effect in this sample. This study confirms the potentially deleterious effect of the e4 allele, in a vulnerable population. The reduced occurrence of the E2 isoform, which is considered to offer a measure of protection against cardiovascular disease, may contribute to the relatively high incidence of coronary heart disease in the South African Indian population. However, the relatively low incidence of the e2 allele may protect this population against the occurrence of type III hyperlipoproteinaemia precipitated by diabetes and obesity in e2/2 homozygotes. / Thesis (M.Med.)-University of Natal, Durban, 1993.

AG to A transition at position -76 in the promoter region of the apoAI gene was previously identified, and the A-76 has been shown to be associated with high apoAI levels. The functional significance of the point mutation was assessed by analysing the DNA-protein binding and promoter activities of the different alleles. This data would suggest that the point mutation alters the function of the apoAI promoter as gel retention assays revealed that the G fragment (-140 to +10) formed an extra DNA-protein complex compared to the A fragment (-140 to +10). Concurrent with the altered DNA-protein interaction between the G and the A fragments, the transcriptional activities of the apoAI gene were found to also be altered. CAT assays have indicated a 1.91 fold increase in promoter activity of the A fragment as compared to the G fragment (-256 to +397). The difference in promoter activity was, however, highly dependent on the particular fragment used, as no difference was observed between the alleles when a fragment {-256 to +68) was used. In this study elements were identified in the region +68 to +397 that causes a reduction in the promoter activity of the G allele by 3.6 fold, whilst reducing the A allele activity by 2 fold. This data would suggest that the point mutation functionally alters the apoAI promoter activity via its interaction with other sequences especially in the region +68 to +397.