Department of Epidemiology, University of Washington, Seattle, WA, USA.
Hum Mol Genet. 2013 Aug 15;22(16):3381-93. doi: 10.1093/hmg/ddt189. Epub 2013 Apr 24.
Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
髓过氧化物酶（MPO）系统水平升高与冠状动脉疾病（CAD）的风险相关。为了确定与循环 MPO 水平相关的遗传因素，我们在欧洲血统和非裔美国人（AA）受试者中进行了全基因组关联研究（GWAS）和基因中心分析。在包含补体因子 H（CFH）基因的 1q31.1 染色体上的一个基因座与 9305 名欧洲血统受试者的血清 MPO 水平强烈相关（主要 SNP rs800292；P=4.89×10(-41))和 1690 名 AA 受试者(rs505102；P=1.05×10(-8))。在 8335 名欧洲血统受试者的基因中心分析中，另外鉴定出两个与血清 MPO 水平相关的罕见 MPO 编码序列变异(rs28730837，P=5.21×10(-12)；rs35897051，P=3.32×10(-8))。在 9260 名欧洲血统受试者的血浆 MPO 水平 GWAS 中，在 MPO 附近的 17q22 染色体上鉴定出一个显著相关的区域（主要 SNP rs6503905；P=2.94×10(-12)），但 CFH 基因座没有证据表明与血浆 MPO 水平相关。功能分析显示 rs800292 与血清中补体蛋白水平相关。17q22 上的变异也对基因表达具有顺式多效性影响。在 CARDIoGRAM 约 80000 名病例对照分析中，没有一个鉴定出的单核苷酸多态性（SNP）与 CAD 相关。这些结果表明，不同的遗传因素调节血清和血浆 MPO 水平，这可能与各种急性和慢性炎症性疾病有关。对于 CAD 的临床意义以及对 CFH 和 MPO 变异与循环 MPO 水平相关的功能基础的更好理解需要进一步研究。
