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首页 » 冠心病 » JAMA:基因分析表明C-反应蛋白与冠心病之间无直接因果关系

JAMA:基因分析表明C-反应蛋白与冠心病之间无直接因果关系

来源:EurekAlert! 2009-07-01 09:17

据7月1日刊JAMA上发表的一项研究披露,一项对炎症生物标记C-反应蛋白(CRP)的遗传变异与冠心病之间的分析无法对它们之间的因果关联给予支持。

冠心病(CHD)是全世界首要的致死原因。 炎症在CHD每个阶段的发展中(即从病理发展的启动到斑块的破裂)都扮演着关键的作用。 根据文章的背景资料,CRP是目前使用最为广泛的炎症生物学标志。 文章的作者写道:“人们对CRP是否与CHD之间存在因果关系,或CRP是否只是动脉粥样硬化基础的一个标记等问题有着相当大的兴趣。”

Imperial College London的Paul Elliott, F.R.C.P.及其同僚开展了一项遗传学的相关性研究,旨在寻找影响CRP水平的共同基因位点(即其染色体上某特别基因的特殊位置)并用基因随机化的方法来检验CRP水平与CHD之间可能存在的因果关系。他们首先开展的是在整个基因组范围内的相关性(n=17,967)和复制研究(n = 13,615)以寻找与血浆CRP浓度相关的基因位点。这些数据的收集时间在1989年至2008年之间,而基因型的决定是在2003年至2008年之间。

研究人员发现:“目前的在基因组范围内的相关性研究证实了LEPR, IL6R, CRP 和HNF1A 位点及APOE-CI-CII 集簇中的普通的基因变异与CRP浓度之间存在着相关性。但是,SNP rs7553007次要等位基因(某基因的一种替代形式)和在纳入我们的孟德尔随机研究中的CRP位点中的其它的变异则与CHD风险之间没有关联。”

研究人员得出结论:“总而言之,我们的对超过28,000例患者样本和100,000例对照样本的孟德尔随机化研究发现,CRP位点变异与CHD之间没有关联性,因此不支持其与粥样硬化中的CRP之间具有因果关系。而且,这一研究提示,开发针对降低血浆CRP浓度的治疗策略不太可能会有效果。”(生物谷Bioon.com)

生物谷推荐原始出处:

JAMA. 2009;302[1]:37-48

Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease

Paul Elliott, FRCP; John C. Chambers, PhD; Weihua Zhang, PhD; Robert Clarke, MD; Jemma C. Hopewell, PhD; John F. Peden, PhD; Jeanette Erdmann, PhD; Peter Braund, MSc; James C. Engert, PhD; Derrick Bennett, PhD; Lachlan Coin, PhD; Deborah Ashby, PhD; Ioanna Tzoulaki, PhD; Ian J. Brown, PhD; Shahrul Mt-Isa, BSc; Mark I. McCarthy, FRCP; Leena Peltonen, MD, PhD; Nelson B. Freimer, MD; Martin Farrall, FRCPath; Aimo Ruokonen, MD, PhD; Anders Hamsten, MD; Noha Lim, PhD; Philippe Froguel, MD; Dawn M. Waterworth, PhD; Peter Vollenweider, MD; Gerard Waeber, MD; Marjo-Riitta Jarvelin, MD; Vincent Mooser, MD; James Scott, FRS; Alistair S. Hall, FRCP; Heribert Schunkert, MD; Sonia S. Anand, MD; Rory Collins, FRCP; Nilesh J. Samani, FRCP; Hugh Watkins, FRCP; Jaspal S. Kooner, FRCP

Context  Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.

Objective  To investigate association of genetic loci with CRP levels and risk of coronary heart disease.

Design, Setting, and Participants  We first carried out a genome-wide association (n = 17 967) and replication study (n = 13 615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28 112 cases and 100 823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14 365 cases and 32 069 controls.

Main Outcome Measure  Risk of coronary heart disease.

Results  Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (–14.8%; 95% confidence interval [CI], –17.6% to –12.0%; P = 6.2 x 10–22), rs4537545 in IL6R (–11.5%; 95% CI, –14.4% to –8.5%; P = 1.3 x 10–12), rs7553007 in the CRP locus (–20.7%; 95% CI, –23.4% to –17.9%; P = 1.3 x 10–38), rs1183910 in HNF1A (–13.8%; 95% CI, –16.6% to –10.9%; P = 1.9 x 10–18), and rs4420638 in APOE-CI-CII (–21.8%; 95% CI, –25.3% to –18.1%; P = 8.1 x 10–26). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, –3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.

Conclusion  The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

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