Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy
Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy
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DOI：
10.1016/s0091-6749(99)70398-2
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发表时间：
1999-08-01
影响因子：
14.2
通讯作者：
Beaty, TH
中科院分区：
文献类型：
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作者：
Barnes, KC;Freidhoff, LR;Beaty, TH
背景：哮喘是一种以过敏性素质的高发和几乎无处不在的上呼吸道疾病(如鼻炎)为特征的复杂疾病。此前，我们观察到非洲裔加勒比家庭的哮喘与12Q染色体上的标志物有关，12Q染色体包含许多编码与过敏性呼吸道炎症和疾病密切相关的产物的基因。目的：为了确定12Q染色体上与上下呼吸道疾病遗传相关的易感基因，并将该区域扩大到编码干扰素-伽马(IFNG)和信号转导和转录激活因子(STAT6)的基因，我们在33个多基因家族中进行了进一步的连锁研究。方法：我们对528名巴巴多斯受试者进行了哮喘特征研究；82%的受试者患有过敏性鼻炎。对22个微卫星标记进行了两点和多点连锁分析。结果受影响的同胞对分析显示在大约30 cM范围内与哮喘有显著的连锁关系(P<；0.05至0.002)，其中12q21.1的第一内含子CA重复多态连锁的证据最好(P=0.002)。在同一区域观察到与变应性鼻炎连锁的证据(分别为D12S313，P=0.006和IFNGCA，P=0.01)。多点关联分析也为哮喘的关联提供了证据，非参数关联分析得分最高的是D12S326(非参数关联得分=3.8，P=.0008)。在D12S1052的D12S326附近观察到与变应性鼻炎连锁的少量证据(P=.036)。结论：(1)染色体12q13.12-q23.3区域的一个或多个基因座参与了临床表型哮喘的表达，最有力的连锁证据是在编码IFNG的基因附近的区域，以及(2)哮喘和变应性鼻炎的易感基因映射到该区域。
Background: Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg, rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease.Objective: To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN-gamma (IFNG) and one of the signal transducers and activators of transcription (STAT6), we conducted further linkage studies among 33 multiplex families.Methods: We characterized 528 subjects from Barbados for asthma; 82% were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning similar to 79 centimorgan) was performed.Results-Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P < .05 to .002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P = .002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = 0.006, and IFNGCA, P = .01, respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric link-age analysis score at D12S326 (nonparametric linkage score = 3.8, P = .0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (P = .036).Conclusions: Our findings suggest that (1) one or more loci in the chromosome 12q13.12-q23.3 region are contributing to the expression of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.