Mack Salome, Coassin Stefan, Rueedi Rico, Yousri Noha A, Seppälä Ilkka, Gieger Christian, Schönherr Sebastian, Forer Lukas, Erhart Gertraud, Marques-Vidal Pedro, Ried Janina S, Waeber Gerard, Bergmann Sven, Dähnhardt Doreen, Stöckl Andrea, Raitakari Olli T, Kähönen Mika, Peters Annette, Meitinger Thomas, Strauch Konstantin, Kedenko Ludmilla, Paulweber Bernhard, Lehtimäki Terho, Hunt Steven C, Vollenweider Peter, Lamina Claudia, Kronenberg Florian
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
J Lipid Res. 2017 Sep;58(9):1834-1844. doi: 10.1194/jlr.M076232. Epub 2017 May 16.
High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the and 1 SNP in the gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the , 1 in the gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, = 3.35 × 10). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the -determining allele of rs7412 to be significantly associated with Lp(a) concentrations ( = 3.47 × 10). Each allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the gene with Lp(a) ( = 3.4 × 10). In summary, we identified a large number of independent SNPs in the gene region, as well as the allele, to be significantly associated with Lp(a) concentrations.
高脂蛋白(a)[Lp(a)]浓度是心血管疾病结局的独立危险因素。浓度受载脂蛋白(a)kringle IV重复异构体的强烈影响。我们旨在利用来自五项全基因组关联研究的数据（n = 13781）确定与Lp(a)浓度相关的基因位点。我们在 基因区域中鉴定出48个独立单核苷酸多态性（SNP）以及1个SNP与Lp(a)浓度显著相关。我们还对载脂蛋白(a)异构体进行了校正，以鉴定独立于它们影响Lp(a)水平的基因位点，结果得到31个SNP（ 基因区域中有30个， 基因区域中有1个）。七个SNP与冠状动脉疾病（CAD）风险呈现全基因组显著关联。一个罕见的SNP（rs186696265；最小等位基因频率约为1%）对Lp(a)的影响最大，并且也与CAD风险增加相关（优势比 = 1.73， = 3.35×10）。随着Lp(a)升高等位基因数量的增加，Lp(a)的中位数从2.1 mg/dl增加到91.1 mg/dl。我们发现rs7412的 决定等位基因与Lp(a)浓度显著相关（ = 3.47×10）。每个 等位基因使Lp(a)降低3.34 mg/dl，相当于人群平均值的约15%。对包括疑似Lp(a)受体和调节因子在内的基因进行关联测试，结果显示 基因与Lp(a)有一个显著关联（ = 3.4×10）。总之，我们在 基因区域以及 等位基因中鉴定出大量与Lp(a)浓度显著相关的独立SNP。
