A pentanucleotide repeat polymorphism in the 5' control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians.

Abstract

The enormous interindividual variation in the plasma concentrations of the atherogenic lipoprotein(a) [Lp(a)] is almost entirely controlled by the apo(a) locus on chromosome 6q26-q27. A variable number of transcribed kringle4 repeats (K4-VNTR) in the gene explains a large fraction of this variation, whereas the rest is presently unexplained. We here have analyzed the effect of the K4-VNTR and of a pentanucleotide repeat polymorphism (TTTTA)n (n = 6-11) in the 5' control region of the apo(a) gene on plasma Lp(a) levels in unrelated healthy Tyroleans (n = 130), Danes (n = 154), and Black South Africans (n = 112). The K4-VNTR had a significant effect on plasma Lp(a) levels in Caucasians and explained 41 and 45% of the variation in Lp(a) plasma concentration in Tyroleans and Danes, respectively.Both, the pentanucleotide repeat (PNR) allele frequencies and their effects on Lp(a) concentrations were heterogeneous among populations. A significant negative correlation between the number of pentanucleotide repeats and the plasma Lp(a) concentration was observed in Tyroleans and Danes. The effect of the 5' PNRP on plasma Lp(a) concentrations was independent from the K4-VNTR and explained from 10 to 14% of the variation in Lp(a) concentrations in Caucasians. No significant effect of the PNRP was present in Black Africans. This suggests allelic association between PNR alleles and sequences affecting Lp(a) levels in Caucasians. Thus, in Caucasians but not in Blacks, concentrations of the atherogenic Lp(a) particle are strongly associated with two repeat polymorphisms in the apo(a) gene. (J. Clin. Invest. 1995. 96:150-157.)

Genetics of the Lp(a)/apo(a) system in an autochthonous Black African population from the Gabon

“…5 Apo(a) size polymorphism was analysed by pulsed-field gel electrophoresis. 34 Three additional polymorphisms at the LPA locus were analysed, as described in the given references: a 5 0 pentanucleotide repeat polymorphism (g.-1417(TTTTA)4 -12) at position -1232, 35 db SNP rs1853021 (g.-49T4C), 36 and db SNP rs1801693 in the IV-10 (g.115618T4C). 37 Apo(a) isoforms were determined by SDS gel electrophoresis and immunodetection, followed by densitometric semiquantitative determination of isoforms as described, 38 and the proportion of Lp(a) associated with each isoform was calculated ( ¼ K IV-allele-associated Lp(a) concentrations).…”

Genetic control of lipoprotein(a) concentrations is different in Africans and Caucasians

“…[16][17][18] There are, however, notable differences in the Lp(a) plasma concentrations as well as in the relation of the K IV VNTR and other intragenic variation to Lp(a) levels across ethnic groups. 19 Lp(a) concentrations are about two to threefold higher in African and American Blacks than in Caucasians. This is neither explained by differences in K IV VNTR frequencies among populations 16,17,20 nor by known differences in other polymorphisms and at present remains unexplained.…”

“…Lp(a) concentrations associated with K IV VNTR alleles of identical size are also different between ethnic groups. 16 A pentanucleotide repeat polymorphism at -1.4 kb in the 5' region of the apo(a) gene is associated with Lp(a) levels in Caucasians but not in Africans 19 and a C/T polymorphism at + 93 affects Lp(a) in Africans but not in Caucasians. 22 In the present study we have used a family and sib-pair approach to analyse to what extent Lp(a) levels are genetically determined in Africans (South African Blacks and Khoi San) and whether there is any contribution of the apo(a) locus beyond the effect of the K IV VNTR in the African populations.…”

Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians

“…Using this technique, 40 alleles from Hong Kong Chinese heterozygous for the KIV CNV by at least three KIV-2 copies difference between their two alleles were subjected to direct haplotyping of non-repetitive exons plus flanking intron sequences in LPA by resequencing, and the 5'PNRP 1372bp upstream of the ATG start codon by polyacrylamide gel electrophoresis [8] (Supplemental Table S1, Supplemental Table S2). These samples had been chosen randomly from the total population sample, from which they neither deviated significantly in KIV CNV size nor Lp(a) concentrations (Kolmogrov-Smirnov test).…”

“…As a consequence of the transcribed and translated KIV-2 copy number variation (KIV-2 CNV), the apolipoprotein(a) protein (apo(a)) displays a size polymorphism [6]. A pentanucleotide repeat polymorphism (5'PNRP) 1372bp upstream of LPA is frequently analysed for more detailed discrimination between LPA alleles but has no effect on gene expression [7,8]. Lp(a) consist of an LDL-like particle attached to apolipoprotein(a).…”