Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease

A high plasma concentration of lipoprotein(a) [Lp(a)] has been suggested as a risk factor for coronary heart disease (CHD), but some recent prospective studies have questioned the significance of Lp(a). Lp(a) concentrations are determined to a large extent by the hypervariable apo(a) gene locus on chromosome 6q2.7, which contains a variable number of identical tandemly arranged transcribed kringle IV type 2 repeats. The number of these repeats correlates inversely with plasma Lp(a) concentration. We analyzed whether apo(a) gene variation (kringle IV repeat number) is associated with CHD. Apo(a) genotypes were determined by pulsed-field gel electrophoresis/genomic blotting in CHD patients who had undergone angiography (n=69) and control subjects matched for age, sex, and ethnicity (n=69) and were related to Lp(a) concentration, apo(a) isoform in plasma, and disease status. Apo(a) alleles with a low kringle IV copy number (<22) and high Lp(a) concentration were significantly more frequent in the CHD group (P<.001), whereas large nonexpressed alleles were more frequent in control subjects. The odds ratio for CHD increased continuously with a decreasing number of kringle IV repeats and ranged from 0.3 in individuals with >25 kringle IV repeats on both alleles to 4.6 in those with <20 repeats on at least one allele. This provides direct genetic evidence that variation at the apo(a) gene locus, which determines Lp(a) levels, is also a determinant of CHD risk.