Apo(a) isoforms predict risk for coronary heart disease. A study in six populations

Elevated concentrations of lipoprotein(a) (Lp[a]) in plasma are associated with premature coronary heart disease (CHD). Lp(a) levels are largely determined by alleles at the hypervariable apolipoprotein(a) (apo[a]) gene locus, but other genetic and environmental factors as well as diseases also affect plasma Lp(a) concentrations. It is therefore unclear whether Lp(a) is a primary genetic risk factor or whether Lp(a) levels are elevated secondary to disease in CHD patients. We have analyzed apo(a) phenotypes that represent a stable genetic trait in subjects with CHD and control subjects from different populations representing a variety of ethnic groups (Tyrol, Germany, Wales, Israel, Singapore Chinese, and Singapore Indian). Despite differences in sampling design and disease definition in this multipopulation case-control study, those apo(a) isoforms associated with high Lp(a) plasma concentrations (B, S1, and S2) were more frequent in the CHD patients in each ethnic group. These differences were significant in three of the studied populations and highly significant (p < 0.001) in the pooled (total) group. Lp(a) concentrations were also measured in all groups except Germans and were found to be consistently higher in cases than in control subjects in each ethnic group. For all but one population (Israeli) the differences were significant. The effects of the apo(a) size polymorphism on Lp(a) levels were similar in CHD patients and control subjects from different populations. The data demonstrate that alleles at the apo(a) locus determine the risk for CHD through their effects on Lp(a) concentrations across multiple populations with large differences in CHD frequency and risk factor profiles.