Polymorphisms in human apolipoprotein(a) kringle IV-10 and coronary arterydisease: relationship to allele size, plasma lipoprotein(a) concentration,and lysine binding site activity

Elevated plasma levels of lipoprotein(a) [Lp(a)] represent a major independ ent risk factor for the development of atherosclerosis. The kringle IV type 10 of apolipoprotein(a) [apo(a)] is the primary lysine binding site (LBS) of Lp(a) and is associated with lesion formation in transgenic mice. The pu rpose of this study was to search for mutations in the apo(a) kringle IV ty pe 10 which could alter the LBS activity of Lp(a) from patients with corona ry artery disease. We found the DNA region of kringle IV type 10 of apo(a) to be mutable but relatively well preserved in the Spanish population. We i dentified a novel mutation which probably leads to a truncated form of apo( a) in a patient heterozygous for the mutation and with low lysine binding a ctivity and low plasma Lp(a) concentration. Two other mutations have been p reviously identified in humans, the substitutions W81R and M75T. The W81R w as not found in our sample, but the M75T mutation was present in 43% of pat ients with coronary artery disease and 23% of age-matched controls. The gen otype TT conferred a significant risk for myocardial infarction (odds ratio 2.53). This association was not due to linkage disequilibrium with kringle IV repeats. The M75T polymorphism was not associated with the LBS function of apo(a), but it influenced plasma Lp(a) concentration.