Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma

BackgroundSex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men.ObjectiveSequence variants in the estrogen receptor α gene (ESR1) may alter estrogen action in asthma.MethodsTwo hundred asthma probands and their families (n = 1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESR1 gene (intervening sequence 1 [IVS1]−1505A/G, IVS1−1415T/C, IVS1−397C/T, IVS1−351G/A and exon1+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.ResultsNo 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.ConclusionESR1 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 implicationsVariations in the gene encoding estrogen receptor α 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.