Barton Sheila J, Koppelman Gerard H, Vonk Judith M, Browning Claudia A, Nolte Ilja M, Stewart Ceri E, Bainbridge Sue, Mutch Stacey, Rose-Zerilli Matthew J, Postma Dirkje S, Maniatis Nikolas, Henry Amanda P, Hall Ian P, Holgate Stephen T, Tighe Patrick, Holloway John W, Sayers Ian
Division of Infection, Inflammation and Immunity, School of Medicine, University of Southampton, Southampton, United Kingdom.
J Allergy Clin Immunol. 2009 Jun;123(6):1391-400.e17. doi: 10.1016/j.jaci.2009.03.014. Epub 2009 May 13.
Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes.
Linkage and association analyses using 587 United Kingdom and Dutch asthma families (n = 2819 subjects) were used to investigate this region.
A 3-phase procedure was used: (1) linkage and association analyses using 15 microsatellite markers spanning 14.4 mega base pairs (Mbps) on 19q13, (2) fine mapping of the refined region using 26 haplotype tagging single nucleotide polymorphisms (SNPs), and (3) dense gene analyses using 18 SNPs evaluated for association with asthma, bronchial hyperresponsiveness (BHR), FEV1, plasma urokinase plasminogen activator receptor (PLAUR), and rate of annual FEV1 decline in subjects with asthma.
The microsatellite analyses provided tentative support for an asthma/lung function susceptibility locus (48.9-49.1Mbps), and fine mapping localized modest association to the PLAUR gene. PLAUR SNPs in the 5' region, intron 3, and 3' region are associated with asthma and BHR susceptibility and predict FEV1 and plasma PLAUR levels. SNPs in the 5' region showed association for asthma (2 populations), FEV1 (2 populations), and BHR (2 populations) phenotypes. SNPs in intron 3 showed association with asthma (2 populations) and BHR (3 populations). Importantly, the same 5' region and intron 3 SNPs were associated with plasma PLAUR levels. The same 5' region and 3' region SNPs were found to be determinants of FEV1 decline in subjects with asthma.
This study represents the first report to identify PLAUR as a potential asthma susceptibility gene and determine PLAUR regions underlying this association, including a role in influencing plasma PLAUR levels. Finally, the association of PLAUR with lung function decline supports a role for PLAUR in airway remodeling in asthma.
多项研究表明,19号染色体19q13.1 - 3区域包含哮喘易感基因。
利用587个英国家庭和荷兰哮喘家庭(共2819名受试者)进行连锁和关联分析,以研究该区域。
采用三阶段程序:(1)使用跨越19q13上14.4兆碱基对(Mbps)的15个微卫星标记进行连锁和关联分析;(2)使用26个单倍型标签单核苷酸多态性(SNP)对精细定位区域进行精细定位;(3)使用18个SNP进行密集基因分析,评估其与哮喘、支气管高反应性(BHR)、第一秒用力呼气容积(FEV1)、血浆尿激酶纤溶酶原激活物受体(PLAUR)以及哮喘患者FEV1年下降率的关联。
微卫星分析为哮喘/肺功能易感基因座(48.9 - 49.1Mbps)提供了初步支持,精细定位发现与PLAUR基因存在适度关联。PLAUR基因5'区域、内含子3和3'区域的SNP与哮喘和BHR易感性相关,并可预测FEV1和血浆PLAUR水平。5'区域的SNP与哮喘(2个群体)、FEV1(2个群体)和BHR(2个群体)表型相关。内含子3中的SNP与哮喘(2个群体)和BHR(3个群体)相关。重要的是,相同区域的5'区域和内含子3的SNP与血浆PLAUR水平相关。相同区域的5'区域和3'区域的SNP被发现是哮喘患者FEV1下降的决定因素。
本研究首次报告将PLAUR鉴定为潜在的哮喘易感基因,并确定了PLAUR与该关联相关的区域,包括其在影响血浆PLAUR水平方面的作用。最后,PLAUR与肺功能下降的关联支持了PLAUR在哮喘气道重塑中的作用。