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

Author:

Lanktree Matthew B.1,Anand Sonia S.1,Yusuf Salim1,Hegele Robert A.1

Affiliation:

1. From the Departments of Medicine and Biochemistry (M.B.L., R.A.H.), Robarts Research Institute and Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada; Population Health Research Institute (S.S.A., S.Y.), Hamilton Health Sciences, and Departments of Medicine and Clinical Epidemiology (S.S.A., S.Y.), McMaster University, Hamilton, Ontario, Canada.

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).

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Genetics(clinical),Cardiology and Cardiovascular Medicine,Genetics

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