Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.
Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.
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DOI：
10.1371/journal.pgen.1000928
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发表时间：
2010-04-29
期刊：
影响因子：
4.5
通讯作者：
McCarthy JJ
中科院分区：
文献类型：
--
作者：
Suchindran S;Rivedal D;Guyton JR;Milledge T;Gao X;Benjamin A;Rowell J;Ginsburg GS;McCarthy JJ
脂蛋白相关磷脂酶A2 （Lp-PLA2）是一个新兴的危险因素和心血管疾病的治疗靶点。这种酶的活性和质量是可遗传的性状，但主要的遗传决定因素尚未在系统的全基因组方式中进行探索。我们对来自基于人群的Framingham心脏研究的6668名高加索受试者进行了Lp-PLA2活性和质量的全基因组关联研究。Affymetrix 550K SNP阵列的临床数据和基因型来自开放获取的Framingham SHARe项目。每个通过质量控制的多态性都使用R统计软件包中实现的线性混合模型来测试与Lp-PLA2活性和质量的关联，考虑家族相关性，并控制年龄、性别、吸烟、降脂药物使用和队列。对于Lp-PLA2活性，4个独立位点的多态性达到全基因组显著性，包括19号染色体上的APOE/APOC1区域（p = 6×10−24）；1号染色体上的CELSR2/PSRC1 (p = 3×10−15)；12号染色体上的SCARB1 （p = 1×10−8）和11号染色体上APOA5/APOA1基因区域的ZNF259/BUD13 （p = 4×10−8）。在考虑了与低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯的关系后，所有这些结果仍然显著。对于Lp-PLA2质量，12个snp具有全基因组显著性，均聚集在染色体6p12.3上靠近PLA2G7基因的区域。我们的分析表明，遗传多态性可能导致Lp-PLA2活性和质量的个体间差异。脂蛋白相关磷脂酶A2 （Lp-PLA2）的血液水平与人类动脉粥样硬化密切相关。这种酶是由免疫系统的某些细胞产生的，与脂蛋白（高密度脂蛋白和低密度脂蛋白）有关，被认为与炎症有关。研究表明，Lp-PLA2是心血管疾病的良好预测因子，独立于HDL和LDL胆固醇水平。这导致了旨在抑制Lp-PLA2的药物的开发，作为治疗或预防心血管疾病的一种方法。Lp-PLA2的活性和质量是可遗传的性状，但主要的遗传决定因素尚未以系统的方式探索。我们检查了人类基因组中的遗传变异，以确定影响Lp-PLA2活性和质量的基因。我们研究了来自基于人群的弗雷明汉心脏研究的6668名高加索受试者。55万个基因变异的临床数据和遗传数据可用于关联分析。活性和质量最显著相关的snp没有重叠。我们确定了与Lp-PLA2活性高度相关的四个不同的基因区域，所有这些区域都已知包括参与胆固醇代谢的基因。唯一与Lp-PLA2质量相关的位点是编码脂蛋白相关磷脂酶A2的基因PLA2G7所在的区域。
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA2 activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA2 activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA2 activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10−24); CELSR2/PSRC1 on chromosome 1 (p = 3×10−15); SCARB1 on chromosome 12 (p = 1×10−8) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10−8). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA2 mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA2 activity and mass. Blood levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) show a strong association with atherosclerosis in humans. This enzyme is made by certain cells of the immune system, associates with lipoproteins (HDL and LDL), and is thought to be involved in inflammation. Studies have shown that Lp-PLA2 is a good predictor of cardiovascular disease, independent of HDL and LDL cholesterol levels. This has led to the development of drugs aimed at inhibiting Lp-PLA2 as a way to treat or prevent cardiovascular disease. The activity and mass of Lp-PLA2 are heritable traits, but major genetic determinants have not been explored in a systematic fashion. We examined genetic variants across the human genome to identify genes influencing Lp-PLA2 activity and mass. We studied 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genetic data on 550,000 genetic variants were available for association analysis. There was no overlap in the most significantly associated SNPs for activity and mass. We identified four distinct gene regions showing highly significant associations with Lp-PLA2 activity, all of which are known to include genes involved in cholesterol metabolism. The only locus associated with Lp-PLA2 mass was a region harboring PLA2G7, the gene that encodes lipoprotein-associated phospholipase A2.
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