Sequence Variation within the KIV-2 Copy Number Polymorphism of the Human LPA Gene in African, Asian, and European Populations

Abstract

Amazingly little sequence variation is reported for the kringle IV 2 copy number variation (KIV 2 CNV) in the human LPA gene. Apart from whole genome sequencing projects, this region has only been analyzed in some detail in samples of European populations. We have performed a systematic resequencing study of the exonic and flanking intron regions within the KIV 2 CNV in 90 alleles from Asian, European, and four different African populations. Alleles have been separated according to their CNV length by pulsed field gel electrophoresis prior to unbiased specific PCR amplification of the target regions. These amplicons covered all KIV 2 copies of an individual allele simultaneously. In addition, cloned amplicons from genomic DNA of an African individual were sequenced. Our data suggest that sequence variation in this genomic region may be higher than previously appreciated. Detection probability of variants appeared to depend on the KIV 2 copy number of the analyzed DNA and on the proportion of copies carrying the variant. Asians had a high frequency of so-called KIV 2 type B and type C (together 70% of alleles), which differ by three or two synonymous substitutions respectively from the reference type A. This is most likely explained by the strong bottleneck suggested to have occurred when modern humans migrated to East Asia. A higher frequency of variable sites was detected in the Africans. In particular, two previously unreported splice site variants were found. One was associated with non-detectable Lp(a). The other was observed at high population frequencies (10% to 40%). Like the KIV 2 type B and C variants, this latter variant was also found in a high proportion of KIV 2 repeats in the affected alleles and in alleles differing in copy numbers. Our findings may have implications for the interpretation of SNP analyses in other repetitive loci of the human genome.

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

“…It is noteworthy that the KIV-2 region itself is still poorly analysed for sequence variations within the repetitive KIV-2 copies. Some variants within KIV-2 units appear to be in LD with KIV-2 CNV size [39].…”

Structure, function, and genetics of lipoprotein (a)

“…The arrow marks the absence of a signal corresponding to the allele with 15 KIV-2 repeats on the Western blot of the individual marked as K5. Figure adapted and reprinted with permission from (200).…”

“…Panels H and I depict possible spreads of variants across the KIV-2 CNV (H) and between KIV-2 copies and the neighboring nonrepetitive KIV-3 (I) by gene conversion. Figure used and modified with permission from (200).…”

“…In a recent study, the coding exons and directly flanking intronic regions of the KIV-2 CNV were sequenced from single alleles of individuals from six populations, including Africans, Europeans, and Asians (200). Several synonymous and nonsynonymous variants, as well as two previously unreported splice site variants, were identified.…”

“…The acceptor splice site variant as well as type B/Cdefining variants were observed at high intra-allelic frequencies (relative proportion of the variant vs. wild-type carrying KIV-2 copies), i.e., they are shared among KIV-2 copies of an allele. Even more intriguing was the observation that similar intra-allelic frequencies were observed for the same variants carried on different sized KIV-2 alleles (200). of biomarkers for various outcomes, which might allow the transition of a risk marker to a risk factor (213).…”