Comprehensive Analysis of Genomic Variation in the LPA Locus and Its Relationship to Plasma Lipoprotein(a) in South Asians, Chinese, and European Caucasians Academic Article uri icon

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abstract

  • Background— Functional copy number variation in the apolipoprotein(a) gene ( LPA ) underlies a variable number of protein kringle domains repeated in tandem in the lipoprotein(a) [Lp(a)] particle. Genomic analysis of LPA , including both single-nucleotide polymorphisms (SNPs) and kringle IV type 2 (KIV-2) copy number, has yet to be performed. Methods and Results— First, we genotyped 49 SNPs within 100 kb of LPA in a multiethnic sample comprising South Asians (n=330), Chinese (n=304), and European Caucasians (n=272). Second, using quantitative polymerase chain reaction, we estimated the KIV-2 copy number in each sample. European Caucasians had the lowest KIV-2 copy number but displayed the strongest correlation between KIV-2 copy number and plasma Lp(a) concentration ( r s =−0.31, P =4.2�10 −7 ). SNP rs10455872, only prevalent in European Caucasians, was strongly associated with both plasma Lp(a) concentration ( P =4.2�10 −29 ) and KIV-2 copy number ( P =7.2�10 −5 ). LPA SNP rs6415084, within the same haplotype block as the KIV-2 variation, was significantly associated with both Lp(a) concentration and KIV-2 copy number in the same direction in all 3 ethnicities [Lp(a), P =5.3�10 −7 ; KIV-2, P =2.6�10 −4 ]. SNPs and KIV-2 copy number together explain a larger proportion of variation in plasma Lp(a) concentrations in European Caucasians (36%) than in Chinese (27%) or South Asians (21%). Conclusions— LPA SNPs are in linkage disequilibrium with KIV-2 copy number, but KIV-2 copy number explains an increment in plasma Lp(a) variation over SNPs alone. Thus, both SNPs and KIV-2 copy number should be included in future genetic epidemiology studies of Lp(a).

publication date

  • February 2010

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