Frequency distributions of apolipoprotein(a) kringle IV repeat alleles and their effects on lipoprotein(a) levels in Caucasian, Asian, and African populations: the distribution of null alleles is non-random.

Abstract

A size polymorphism (K IV VNTR) and largely unknown sequence variation in the apolipoprotein(a) [apo(a)] gene on chromosome 6q26-q27 together determine most of the extreme variation in apo(a) glycoprotein expression and lipoprotein(a) [Lp(a)] plasma concentration in Caucasians. We have determined Lp(a) plasma concentrations, the number of kringle IV (K IV) repeats in the apo(a) gene and the expression of the apo(a) glycoprotein in four ethnic groups (Khoi San, South African Blacks, Hong Kong Chinese and Caucasians from the Tyrol, total n = 788). The distributions of Lp(a) concentrations, the frequencies of expressed and non-expressed apo(a) K IV alleles, and the impact of the size polymorphism on Lp(a) concentrations were all heterogeneous across populations. In contrast, the effect of the K IV repeat alleles appeared homogeneous. Lp(a) concentrations were higher in Africans and Chinese than in Caucasians, but this was not explained by differences in K IV repeat allele frequencies among populations. Lp(a) concentrations were highest in Khoi San, suggesting that high Lp(a) is an old African trait. When expressed as Spearman rank correlations the impact of the size polymorphism was smallest in African Blacks (R = -0.386) and largest in the Chinese (R = -0.692). In all four populations, the distribution of non-expressed apo(a) alleles was non-random. Rather they were significantly associated with distinct size alleles and overall positively with high K IV repeat numbers. The negative correlation of K IV repeat length with Lp(a) concentration was non-linear in Khoi San and the average apo(a)-size-allele-associated Lp(a) concentrations were markedly different between all populations. We conclude that besides the apo(a) size variation, other factors affect Lp(a) concentrations to different degrees in the study populations. Most likely, this is sequence variation in apo(a) which is not the same in the different ethnic groups.