The APO(a) size and PNR polymorphisms explain differences in allele-specific APO(a) levels between African Americans and Caucasians for small APO(a) but not large APO(a) sizes

Jill Rubin, Han Jo Kim, Thomas A. Pearson, Steve Holleran, Rajasekhar Ramakrishnan, and Lars Berglund

Medicine Dept., University of California Davis, Sacramento, CA 95817

Corresponding Author: lars.berglund{at}ucdmc.ucdavis.edu

Objective: Apo(a) gene size is a major predictor of Lp(a) level, a cardiovascular risk factor with large differences between Caucasians and African Americans. To determine genetic predictors of allele-specific apo(a) levels beyond gene size, we evaluated the upstream C/T and PNR polymorphisms. Methods and Results: We determined apo(a) sizes, allele-specific apo(a) levels (i.e. levels associated with alleles defined by size) and the C/T and PNR polymorphisms in 354 men and women (215 Caucasians and 139 African Americans). For Caucasians, the effect of apo(a) size on allele-specific levels was substantially greater in subjects with gene size below 24 K4; for African Americans, the size effect was smaller than in Caucasians below 24 K4 but did not decrease at higher repeats. In both groups the level decreased with increasing size of the other allele. Controlling for apo(a) sizes, PNR influenced allele-specific apo(a) levels in Caucasians, with a stepwise decrease with increasing PNR number >8. The C/T polymorphism had no independent effect on apo(a) levels in either group. In a multiple regression model, apo(a) allele size, the size and expression of the other apo(a) allele (and PNR >8 for Caucasians) significantly predicted allele-specific apo(a) levels. For a common PNR 8 allele, predicted values were similar in the two ethnicities for small-size apo(a) but different otherwise. Conclusion: Allele-specific apo(a) levels were influenced by the other allele size and expression. Observed differences between Caucasians and African Americans in allele-specific apo(a) levels were explained for small apo(a) sizes by the other allele size and the PNR polymorphism; the decrease in levels with size was much greater for Caucasians so the ethnicity differences remain unexplained for larger sizes.

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