在一项针对17686名女性的纤维蛋白原全基因组关联研究中发现的新基因座，包括与克罗恩病、银屑病和炎症相关的基因座：女性基因组健康研究。
Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study.
作者信息
Danik Jacqueline S, Paré Guillaume, Chasman Daniel I, Zee Robert Y L, Kwiatkowski David J, Parker Alex, Miletich Joseph P, Ridker Paul M
机构信息
Center for Cardiovascular Disease Prevention, Donald W. Reynolds Center for Cardiovascular Research, and Translational Medicine Division, Brigham and Women's Hospital, 900 Commonwealth Ave. East, Boston, MA 02215, USA.
出版信息
Circ Cardiovasc Genet. 2009 Apr;2(2):134-41. doi: 10.1161/CIRCGENETICS.108.825273. Epub 2009 Feb 12.
BACKGROUND
Fibrinogen is a multifunctional circulating glycoprotein involved in wound healing, thrombosis, platelet aggregation, and inflammation, and elevated levels predict vascular disease. Despite evidence of crucial biological function and moderate heritability, comprehensive analysis of the influence of genetic variation on fibrinogen is not available.
METHODS AND RESULTS
To address this issue, we undertook a genome-wide association study evaluating the potential relationships between 337 343 single-nucleotide polymorphisms (SNPs) and plasma fibrinogen levels among 17 686 apparently healthy women participating in the Women's Genome Health Study. As C-reactive protein is also an inflammatory marker known to predict cardiovascular diseases, we compared the determinants of fibrinogen levels with those of C-reactive protein. Four novel loci were identified, in addition to the fibrinogen gene cluster, which were associated with fibrinogen levels at genome-wide levels of significance (range of probability values from 8.82 x 10(-09) to 8.04 x 10(-39)). Two of the loci are related to common chronic inflammatory diseases: the first, at locus 5q31.1 (SLC22A5, SLC22A4, IRF1), lies immediately adjacent to a locus linked to Crohn disease (P value for lead SNP, 1.24 x 10(-12)) and the second, at locus 17q25.1 (CD300LF, SLC9A3R1, NAT9), has been associated with psoriasis (P value for lead SNP, 7.72 x 10(-11)). A third locus at 1q21.3 (IL6R) lies within the interleukin 6 receptor gene, a critical component of the inflammatory cascade (P value for lead SNP, 1.80 x 10(-11)). A novel locus at 2q34 (CPSI) participates in the urea cycle (P=8.82 x 10(-09)). The majority of implicated SNPs showed little evidence of dual association with C-reactive protein levels.
CONCLUSIONS
A genome-wide survey of the human genome identifies novel loci related to common chronic inflammatory diseases as genetic determinants of fibrinogen levels, in addition to loci that relate to the inflammatory cascade, the urea cycle, and the fibrinogen gene cluster.
背景
纤维蛋白原是一种多功能循环糖蛋白，参与伤口愈合、血栓形成、血小板聚集和炎症反应，其水平升高预示着血管疾病。尽管有证据表明其具有关键的生物学功能且具有中等遗传性，但目前尚无关于基因变异对纤维蛋白原影响的全面分析。
方法与结果
为解决这一问题，我们开展了一项全基因组关联研究，评估参与女性基因组健康研究的17686名表面健康女性中337343个单核苷酸多态性（SNP）与血浆纤维蛋白原水平之间的潜在关系。由于C反应蛋白也是一种已知可预测心血管疾病的炎症标志物，我们比较了纤维蛋白原水平的决定因素与C反应蛋白的决定因素。除纤维蛋白原基因簇外，还发现了四个新的基因座，它们在全基因组显著水平上与纤维蛋白原水平相关（概率值范围为8.82×10⁻⁹至8.04×10⁻³⁹）。其中两个基因座与常见的慢性炎症性疾病有关：第一个位于5q31.1基因座（SLC22A5、SLC22A4、IRF1），紧邻与克罗恩病相关的基因座（领先SNP的P值为1.24×10⁻¹²）；第二个位于17q25.1基因座（CD300LF、SLC9A3R1、NAT9），与银屑病有关（领先SNP的P值为7.72×10⁻¹¹）。位于1q21.3的第三个基因座（IL6R）位于白细胞介素6受体基因内，是炎症级联反应的关键组成部分（领先SNP的P值为1.80×10⁻¹¹）。位于2q34的一个新基因座（CPSI）参与尿素循环（P = 8.82×10⁻⁹）。大多数相关SNP几乎没有证据表明与C反应蛋白水平存在双重关联。
结论
对人类基因组进行全基因组调查发现，除了与炎症级联反应、尿素循环和纤维蛋白原基因簇相关的基因座外，还发现了与常见慢性炎症性疾病相关的新基因座，这些基因座是纤维蛋白原水平的遗传决定因素。
Zotero 插件