Lanktree Matthew B, Anand Sonia S, Yusuf Salim, Hegele Robert A
Department of Medicine and Biochemistry, Robarts Research Institute and Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Circ Cardiovasc Genet. 2010 Feb;3(1):39-46. doi: 10.1161/CIRCGENETICS.109.907642. Epub 2009 Dec 30.
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.
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%).
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).
载脂蛋白(a)基因（LPA）中的功能性拷贝数变异是脂蛋白(a) [Lp(a)]颗粒中串联重复的不同数量的蛋白kringle结构域的基础。尚未对LPA进行基因组分析，包括单核苷酸多态性（SNP）和kringle IV 2型（KIV-2）拷贝数。
首先，我们在一个多民族样本中对LPA 100 kb范围内的49个SNP进行基因分型，该样本包括南亚人（n = 330）、中国人（n = 304）和欧洲白种人（n = 272）。其次，使用定量聚合酶链反应，我们估计了每个样本中的KIV-2拷贝数。欧洲白种人的KIV-2拷贝数最低，但KIV-2拷贝数与血浆Lp(a)浓度之间的相关性最强（r(s)= -0.31，P = 4.2×10(-7)）。SNP rs10455872仅在欧洲白种人中普遍存在，与血浆Lp(a)浓度（P = 4.2×10(-29)）和KIV-2拷贝数（P = 7.2×10(-5)）均密切相关。与KIV-2变异处于同一单倍型块内的LPA SNP rs6415084在所有3个种族中与Lp(a)浓度和KIV-2拷贝数均呈相同方向的显著相关[Lp(a)，P = 5.3×10(-7)；KIV-2，P = 2.6×10(-4)]。SNP和KIV-2拷贝数共同解释的欧洲白种人血浆Lp(a)浓度变异比例（36%）高于中国人（27%）或南亚人（21%）。
LPA SNP与KIV-2拷贝数处于连锁不平衡状态，但KIV-2拷贝数单独解释血浆Lp(a)变异的增量超过SNP。因此，在未来关于Lp(a)的遗传流行病学研究中应同时纳入SNP和KIV-2拷贝数。
