Kozlowski Piotr, Miller David T, Zee Robert Y L, Danik Jacqueline Suk, Chasman Daniel I, Lazarus Ross, Cook Nancy R, Ridker Paul M, Kwiatkowski David J
Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Ann Hum Genet. 2006 Sep;70(Pt 5):574-86. doi: 10.1111/j.1469-1809.2005.00256.x.
It is well-known that baseline levels of C-reactive protein (CRP) are an independent cardiovascular risk factor. We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system. We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes (CARD15, IRAK1, IRAK4, LBP, LY86, MEFV, TLR2, TLR4 and NFKB1) in relation to CRP levels. Seven hundred and seventeen subjects from the Women's Health Study population were studied: 359 and 358 samples with extremely low (<0.2 mg/liter) and high (>5 mg/liter) CRP levels, respectively. SNPs were identified from publicly available resequencing data, using a minor allele frequency threshold of >5% and a linkage disequilibrium (LD)-based strategy (r(2) > 0.8) to select 63 LD-independent markers. One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied. Univariate, haplotype and gene-gene interaction analyses all indicated no significant association with CRP levels. Although this work excludes a significant association of common SNPs in these nine genes with CRP levels, it is possible that rarer alleles in these genes, or variation in other innate immunity genes, could be associated with variation in CRP.
众所周知，C反应蛋白（CRP）的基线水平是一个独立的心血管危险因素。我们推测，可能会在先天免疫系统的基因中发现对CRP水平有显著影响的基因变异。我们进行了一项候选基因关联研究，检测9个先天免疫基因（CARD15、IRAK1、IRAK4、LBP、LY86、MEFV、TLR2、TLR4和NFKB1）中的常见单核苷酸多态性与CRP水平的关系。对来自女性健康研究人群的717名受试者进行了研究：分别有359个和358个样本的CRP水平极低（<0.2毫克/升）和极高（>5毫克/升）。单核苷酸多态性（SNPs）是从公开的重测序数据中识别出来的，使用次要等位基因频率阈值>5%和基于连锁不平衡（LD）的策略（r(2)>0.8）来选择63个LD独立标记。还研究了TLR4中的一个非同义单核苷酸多态性和CARD15中的两个非同义单核苷酸多态性，它们之前分别与动脉粥样硬化和克罗恩病有关。单变量、单倍型和基因-基因相互作用分析均表明与CRP水平无显著关联。尽管这项研究排除了这9个基因中的常见单核苷酸多态性与CRP水平的显著关联，但这些基因中更罕见的等位基因，或其他先天免疫基因的变异，有可能与CRP的变异有关。
