SEQUENCE MICROHETEROGENEITY IN APOLIPOPROTEIN(A) GENE REPEATS AND THERELATIONSHIP TO PLASMA LP(A) LEVELS

Lipoprotein(a) [Lp(a)] is a cholesterol ester-rich atherogenic lipopro tein that is composed of a particle of low density lipoprotein and a l arge glycoprotein, apolipoprotein(a) [apo(a)]. Apolipoprotein(a) varie s in size over a similar to 500 kDa range due to inter-allelic differe nces in the number of tandemly repeated kringle 4 (K4)-encoding 5.5 kb sequences in the apo(a) gene, Only one of the 10 different types of K 4 repeats in the apo(a) gene, the so-called type 2 K4 repeats, vary in number between apo(a) alleles. In this paper, we show that there is m icroheterogeneity within the sequence of the type 2 K4 repeat. DraIII restriction digestion and genomic blotting revealed that a subset of t he type 2 K4-encoding sequences contained a DraIII site (K4-D). The pr oportion of apo(a) alleles that had at least one K4-D repeat ranged fr om 25% in Caucasians to 50% in the Chinese, K4-D repeats were clustere d at the end(s) of the type 2 K4 tandem array and the number and patte rns of the K4-D repeats were in linkage disequilibrium with flanking s equence polymorphisms; these features are remarkably similar to the mi nisatellite variant repeats (MVRs) found in variable number of tandem repeat sequences (VNTRs). In addition, a DraIII pattern that comprised 9% of the sample was invariably associated with low plasma levels of Lp(a) in Caucasians.