Lipoprotein(a), atherosclerosis, and apolipoprotein(a) gene polymorphism

High plasma lipoprotein(a) [Lp(a)] levels have been implicated as an independent risk factor for coronary artery disease in Caucasians, Chinese, Africans, and Indians. Apo(a) that evolved from a duplicated plasminogen gene during recent primate evolution is responsible for the concentration of Lp(a) in the artery waif. leading to atherosclerosis, by virtue of its ability to bind to the extracellular matrix and its role in stimulating the proliferation and migration of human smooth muscle cells. Several types of polymorphisms, size as well as sequence changes both in the coding and regulatory sequences, have been reported to influence the variability of Lp(a) concentration. Apo(a) exhibits genetic size polymorphism varying between 300 and 800 kDa that could be attributed to the number of k-4 VNTR (variable number of transcribed kringle-4 repeats). An inverse relationship between Lp(a) level and apo(a) allele sizes is a general trend in all ethnic populations although apo(a) allele size distribution could be significantly variable in ethnic types. A negative correlation between the number of pentanucleotide TTTTA(n) repeat (PNR) sequences in the regulatory region of the apo(a) gene and Lp(a) level has also been observed in Caucasians and Indians, but not in African Americans. However, a significant linkage disequilibrium was noted between the PNR number and k-4 VNTR. In order to correlate the role of apo(a) gene polymorphisms to apo(a) gene regulation, we have proposed that liver-specific transcriptional activators and repressors might contribute to the differential expression of apo(a) gene, in an individual-specific manner. (C) 2000 Academic Press.