GENOMIC STRUCTURE AND ORGANIZATION OF KRINGLES TYPE-3 TO TYPE-10 OF THE APOLIPOPROTEIN(A) GENE IN 6Q26-27

Apolipoprotein(a) [apo(a)] is a highly polymorphic glycoprotein covale ntly linked to the apolipoprotein B-100 of LDL in a particle called li poprotein(a) [Lp(a)]. High plasma levels of Lp(a) are associated with coronary as well as peripheral atherosclerosis. Plasma levels of Lp(a) show a remarkable variation ranging from 0.1 mg/dl to over 100 mg/dl. The apo(a) gene shows a size polymorphism which resides in the variab le number of kringle domains which resemble plasminogen kringle IV. Te n different types of kringle IV repeats have been described, nine of w hich (kringle IV type 1 and type 3-10) are each supposed to be present in a single copy. The other kringles, namely kringle IV type 2 repeat s, vary in number from 3 to 42 between apo(a) alleles and form the bas is for the apo(a) size polymorphism. Although an inverse relationship has been observed between the number of kringle type 2 repeats and pla sma levels of Lp(a), there are exceptions to this general finding. Ind eed, several individuals have been described with similar apo(a) size alleles but very different plasma levels of Lp (a). Genetic studies ha ve linked these differences to the apo(a) locus on 6q26-27, outlining the importance, besides the kringle type 2 repeats, of other regions o f the apo(a) gene in contributing to the interindividual differences i n the plasma concentration of Lp(a). One of the candidate regions is r epresented by the non-repeated type-3 to type-10 kringles which are in variably present in each apo(a) allele and whose structural integrity is playing a critical role in the correct assembly of the Lp(a) partic le. Biochemical studies with recombinant wild type and mutagenized apo (a) cDNAs with several alterations of the non-repeated kringles have w ell documented this latter point. As a starting point to search for ge netic variations in these kringles associated with different levels of Lp(a), we are presenting the genome organization of type-3 to 10 krin gle along with specific PCR primers for easy analysis from genomic DNA . Restriction as well as partial sequencing analyses of the type-3 to 10 kringles region has also provided interesting clues as to the diffe rent evolutionary origin of these types of kringle with respect to the polymorphic type-2 kringles. (C) 1997 Elsevier Science B.V.