Molecular genetics of lipoprotein(a)
The work presented in this thesis aims to extend our understanding of controlling mechanisms that influence the plasma concentration of lipoprotein(a) [LP(a)]. The techniques of apo(a) genotyping and apo(a) phenotyping are used to study Lp(a) in different ethnic and genetic groups to achieve this end. In chapter 3 the effective use of a commercially available monoclonal antibody is demonstrated. Two primary antibodies were compared and apo(a) isoform analysis was performed using an immunoblotting method. With both monoclonals it was possible to detect 0.05mg. dL-1 Lp(a). Distributions of plasma Lp(a) concentrations exhibit marked inter-racial differences. Apo(a), the unique constituent of Lp(a), is highly polymorphic in length due to allelic variations in the number of kringle 4 (K-4)-encoding sequences. Plasma Lp(a) concentrations are inversely related to the number of K-4 repeats in the apo(a) alleles. To determine the contribution of this length variation to the inter-racial variation in plasma Lp(a) levels, the APO(a) allele size, glycoprotein size, and plasma Lp(a) concentrations in Caucasians, Chinese and African-Americans were compared in chapter 4. Caucasians and African-Americans had very different distributions of plasma Lp(a) concentrations yet there was no significant difference in the overall frequency distributions of their APO(a) alleles. Over the entire size spectrum of apo(a) alleles, the plasma Lp(a) levels were higher in African-Americans that in Caucasians. Conversely, Caucasians and Chinese had similar plasma Lp(a) concentrations, but significantly different APO(a) allele size distributions. Therefore, inter-racial differences in plasma concentrations of Lp(a) are not due to differences in the frequency distributions of APO(a) alleles. The relationship between APO(a) allele size and the presence of detectable plasma apo(a) protein in plasma were also examined. APO(a) alleles associated with no detectable plasma protein were not of uniformly large size, as had been expected, but were distributed over the entire size spectrum. From this analysis, it was concluded that there is no common "null" allele at the APO(a) locus.