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Plasma lipoprotein [a] (Lp[a]) concentrations are inversely associated with, and largely determined by, apolipoprotein [a] (apo[a]) gene size, a highly polymorphic trait. We studied if, within an individual, the smaller apo[a] isoform always dominated, whether there was interaction between the two alleles, and whether these features differed between Caucasians and African Americans. We determined apo[a] gene sizes, apo[a] protein sizes and relative amounts, and plasma Lp[a] levels in 430 individuals (263 Caucasians and 167 African Americans). Of the 397 heterozygotes with at least one detectable apo[a] isoform (238 Caucasians and 159 African Americans), the larger allele dominated in 28% of Caucasians and 23% of African Americans, while the smaller allele dominated in 56% of Caucasians and 45% of African Americans. In Caucasians, dominance of the smaller allele increased with Lp[a] levels, from 44% at Lp[a] < or = 30 nM to 81% at Lp[a] >100 nM (P < 0.0001). Dominance by the smaller allele increased with increasing size of the larger allele in both groups but with the smaller allele only in African Americans. There was no interaction between apo[a] alleles within genotypes; one apo[a] isoform level was not associated with the other isoform level, and isoform levels were not affected by the difference in size. More of the dominance pattern was explained by Lp[a] level and apo[a] genotype in African Americans than in Caucasians (29% vs. 13%). Thus, genotype influences isoform-specific Lp[a] levels and dominance patterns differently in African Americans and in Caucasians.

Lipoprotein(a) [Lp(a)] is a novel risk factor for atherosclerosis, whose role in multiracial populations has been debated. We recently demonstrated a significant association of elevated levels of Lp(a) carried in particles containing small apolipoprotein(a) [apo(a)] isoforms with coronary artery disease in African American and white men. To extend these findings, we investigated the associations between Lp(a) levels, apo(a) size, and maximum internal carotid artery plaque thickness (MPT) in a randomly selected elderly multiethnic population (173 men and 253 women, consisting of 135 African Americans, 146 Hispanics, and 145 whites; mean age 70.5+/-11.4 years). Lp(a) levels were not associated with MPT. Among white men, MPT was associated with a small apo(a) isoform size (P=0.03) as well as with the amount of Lp(a) carrying the small apo(a) size (P=0.04), and the latter showed a borderline association in African American men (P=0.07). Among white women, but not in Hispanic or African American women, MPT was associated with the amount of Lp(a) carrying a small apo(a) isoform size (P<0.01). For all patients, the amount of Lp(a) carrying the small apo(a) size was associated with carotid atherosclerosis when there was control for age, sex, ethnicity, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, diabetes mellitus, hypertension, waist-to-hip ratio, and current smoking status (P=0.03). This association was significant for all men (P=0.03) and for white women (P=0.007). The results suggest that molecular properties of apo(a) are important in determining the atherogenicity of Lp(a).