title: Comprehensive analysis of genomic variation in the LPA locus and its relationship to plasma lipoprotein(a) in South Asians, Chinese, and European Caucasians.
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.
  
  
  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 x 10(-7)). SNP rs10455872, only prevalent in European Caucasians, was strongly associated with both plasma Lp(a) concentration (P=4.2 x 10(-29)) and KIV-2 copy number (P=7.2 x 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 x 10(-7); KIV-2, P=2.6 x 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).
authors.affiliation: Department of Medicine and Biochemistry, Robarts Research Institute and Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Lanktree
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Anand
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D053241:Apoprotein(a) / Q000097:blood / Q000235:genetics*; D001211:Asia, Western; D044466:Asian People / Q000235:genetics*; D002681:China; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D018082:Kringles / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics*
chemical_list: D053241:Apoprotein(a)