哮喘的遗传易感性——支气管高反应性与特应性主基因共同遗传。

Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy.

作者信息

Postma D S, Bleecker E R, Amelung P J, Holroyd K J, Xu J, Panhuysen C I, Meyers D A, Levitt R C

机构信息

University Hospital, Groningen, The Netherlands.

出版信息

N Engl J Med. 1995 Oct 5;333(14):894-900. doi: 10.1056/NEJM199510053331402.

DOI:10.1056/NEJM199510053331402

PMID:7666875

Abstract

BACKGROUND

Bronchial hyperresponsiveness, a risk factor for asthma, consists of a heightened bronchoconstrictor response to a variety of stimuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relations is unknown, as is the mechanism of genetic susceptibility to bronchial hyperresponsiveness. We attempted to define the interrelation between atopy and bronchial hyperresponsiveness and to investigate the chromosomal location of this component of asthma.

METHODS

We studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial responsiveness to histamine, and serum total IgE were measured. The association between the last two variables was evaluated. Using analyses involving pairs of siblings, we tested for linkage between bronchial hyperresponsiveness and genetic markers on chromosome 5q31-q33, previously shown to be linked to a genetic locus regulating serum total IgE levels.

RESULTS

Serum total IgE levels were strongly correlated (r = 0.65, P < 0.01) in pairs of siblings concordant for bronchial hyperresponsiveness (defined as a > or = 20 percent decrease in the forced expiratory volume in one second produced by histamine [threshold dose, < or = 16 mg per milliliter]), suggesting that these traits are coinherited. However, bronchial hyperresponsiveness was not correlated with serum IgE levels (r = 0.04, P > 0.10). Analyses of pairs of siblings showed linkage of bronchial hyperresponsiveness with several genetic markers on chromosome 5q, including D5S436 (P < 0.001 for a histamine threshold value of < or = 16 mg per milliliter).

CONCLUSIONS

This study demonstrates that a trait for an elevated level of serum total IgE is coinherited with a trait for bronchial hyperresponsiveness and that a gene governing bronchial hyperresponsiveness is located near a major locus that regulates serum IgE levels on chromosome 5q. These findings are consistent with the existence of one or more genes on chromosome 5q31-q33 causing susceptibility to asthma.

摘要

背景

支气管高反应性是哮喘的一个危险因素，表现为对多种刺激的支气管收缩反应增强。该病症具有遗传成分，且与血清IgE水平及气道炎症密切相关。这些关系的基础尚不清楚，支气管高反应性的遗传易感性机制也不明确。我们试图明确特应性与支气管高反应性之间的相互关系，并研究哮喘这一组成部分在染色体上的定位。

方法

我们研究了从荷兰一个同质化人群中选取的84名哮喘先证者的303名子女和孙子女。测量了通气功能、支气管对组胺的反应性以及血清总IgE水平。评估了后两个变量之间的关联。通过对同胞对的分析，我们检测了支气管高反应性与5号染色体q31 - q33上的遗传标记之间的连锁关系，此前已表明该区域与调节血清总IgE水平的基因座连锁。

结果

对于支气管高反应性一致的同胞对（定义为组胺导致一秒用力呼气量下降≥20%[阈值剂量，≤16毫克/毫升]），血清总IgE水平高度相关（r = 0.65，P < 0.01），表明这些性状是共同遗传的。然而，支气管高反应性与血清IgE水平不相关（r = 0.04，P > 0.10）。对同胞对的分析显示支气管高反应性与5号染色体q上的几个遗传标记存在连锁关系，包括D5S436（对于组胺阈值≤16毫克/毫升，P < 0.001）。