Genetic architecture and evolution of the lipoprotein(a) trait.

Apolipoprotein(a) is coded by one of the most polymorphic genes known in humans. In white and Asian populations variation in this gene is the major determinant of the plasma concentrations of the atherogenic lipoprotein(a) which varies enormously between individuals and considerably across populations. Recent studies have shown that the genetic architecture of the quantitative Lp(a) trait differs among major human groups. In Africans there is evidence for a transacting factor. Three types of variation have been identified in the apo(a) gene: a size polymorphism in the coding region (K IV type 2 repeats), a pentanucleotide repeat polymorphism in the promoter (5'PNRP) and sequence variation in coding and non-coding regions of the gene including a C/T polymorphism at +93 which creates an additional ATG start codon but also affects transcription. The causal +93 C/T effect is masked by linkage disequilibrium in white populations. Analysis of apo(a) K IV 6-10 exons revealed the existence of population-specific spectra of polymorphism in this domain. However further sequence variation which may provide clues for the understanding of the regulation of apo(a) concentrations still needs to be identified. DNA sequencing and phylogenetic analysis have demonstrated that two types of apo(a) exist, in phylogenetically distant mammalian lineages a K IV derived primate form and a K III-derived hedgehog form which are products of convergent evolution.