Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma
Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma
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DOI：
10.1016/j.jaci.2005.11.023
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发表时间：
2006-03-01
影响因子：
14.2
通讯作者：
Postma, DS
中科院分区：
文献类型：
--
作者：
Dijkstra, A;Howard, TD;Postma, DS
背景资料：目的：雌激素受体A基因（ESRI）序列变异可能改变雌激素在哮喘中的作用。200名哮喘先证者及其家属对1249例ESRI基因的5个单核苷酸多态性（SNPs）进行基因分型（间插序列1 [IVS 1]-1505 A/G，IVS 1 - 1415 T/C，IVS 1 - 397 C/T，IVS 1 - 351 G/A和外显子1 + 30 T/C）。测试了与哮喘和支气管高反应性（BHR）的相关性。在哮喘先证者中，SNPs与BHR严重程度和FEV 1年下降的相关性被确定。IVS 1 -397与BHR的存在显著相关（P =.02），并与性别相互作用; CT或TT基因型的女性受试者有风险（P =.01）。在哮喘先证者中，所有SNP均与FEV 1下降相关。与CC组相比，外显子1 + 30 CT和TT组分别有11.6 mL/y（P =.03）和15.7 mL/y（P =.01）的过度下降。在IVS 1多态性中，IVS 1 - 351 G/A显示出最强的关联，与GG组相比，AA组的过度下降为16.1 mL/y（P =.01）。在按性别进行的亚组分析中，这些协会仅在女性subjects.Conclusion显着：ESR 1基因变异可能会影响BHR的发展，特别是在女性subjects。它们还可能导致哮喘患者更快的肺功能丧失，特别是女性受试者。这可能是由于雌激素作用改变，影响肺发育和/或气道重塑。对ESR 1基因变异的进一步研究对于更好地理解哮喘性别差异的起源非常重要。临床意义：编码雌激素受体a的基因变异与BHR和更快的年度肺功能下降相关，尤其是女性受试者。尽管这没有诊断或临床意义，但它可能为未来哮喘的性别特异性治疗开辟道路。
Background: Sex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men.Objective: Sequence variants in the estrogen receptor a gene (ESRI) may alter estrogen action in asthma.Methods: Two hundred asthma probands and their families (n = 1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESRI gene (intervening sequence 1 [IVS1]-1505A/G, IVS1-1415T/C, IVS1-397C/T, IVS1-351G/A and exon 1 +30T/C). Association with asthma and bronchial hyperresponsiveness (BHR) were tested. In the asthma probands, association of SNPs with BHR severity and annual FEV1 decline were determined.Results: No SNP was associated with asthma. IVS1-397 was significantly associated with the presence of BHR (P =.02) and interacted with sex; female subjects with the CT or TT genotype were at risk (P =.01). In asthma probands, all SNPs were associated with FEV1 decline. Exon1 +30 CT and TT group had an excess decline of 11.6 mL/y (P =.03) and 15.7 mL/y (P =.01), respectively, compared with the CC group. Of the IVS1 polymorphisms, IVS1-351G/A showed the strongest association, with the AA group having excess decline of 16.1 mL/y (P =.01) compared with the GG group. In subanalyses by sex, these associations were significant only in female subjects.Conclusion: ESR1 gene variants may affect development of BHR, particularly in female subjects. They may also lead to a more rapid lung function loss in patients with asthma, and in female subjects specifically. This may result from altered estrogen action, which affects lung development and/or airway remodeling. Further studies on ESR1 gene variations are important to understand better the origin of sex differences in asthma. Clinical implications: Variations in the gene encoding estrogen receptor a are associated with BHR and a more rapid annual lung function decline., especially in female subjects. Even though this has no diagnostic or clinical implication, it may open avenues for future sex-specific treatment in asthma.