Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians

Lipoprotein(a) [Lp(a)] is a complex of apolipoprotein(a) [apo(a)l and low-d ensity lipoprotein which is associated with atherothrombotic disease. Lp(a) plasma levels are controlled to a large extent by the apo(a) gene locus. K nown polymorphisms in the apo(a) gene, including the kringle (K) IV-2 varia ble number of tandem repeats, explain only part of the large interindividua l variability and do not explain the differences in Lp(a) concentrations be tween major human ethnic groups, Here we performed screening for single nuc leotide polymorphisms (SNPs) in exons and flanking intron sequences of the apo(a) K IV types 6, 8, 9 and 10 which represent 1.3 kb of coding sequence in two African (Khoi San, Black South Africans) and one Caucasian (Tyrolean s) populations and investigated whether they affect Lp(a) levels, Together, 768 alleles were analyzed, We identified 14 SNPs, including 11 non-synonym ous SNPs (eight of which involved conserved residues), one splice site and two synonymous base changes. No sequence variants common to Africans and Ca ucasians were found. Several of the newly identified SNPs showed significan t effects on Lp(a) plasma concentrations. The substitutions S37F in K IV-6 and G17R in K IV-8 were associated with Lp(a) levels significantly below av erage in Africans. In contrast, the R18W substitution in K IV-9, which occu rred with a frequency of 8% in Khoi San, resulted in a significantly increa sed Lp(a) concentration. Together, our data suggest that several SNPs in th e coding sequence of apo(a) affect Lp(a) levels. This indicates that many S NPs may have subtle effects on the gene product.