TY - JOUR
T1 - Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma
AU - Dijkstra, Antoon
AU - Howard, Timothy D.
AU - Vonk, Judith M.
AU - Ampleford, Elizabeth J.
AU - Lange, Leslie A.
AU - Bleecker, Eugene R.
AU - Meyers, Deborah A.
AU - Postma, Dirkje S.
N1 - Funding Information:
Supported by The Netherlands Asthma Foundation (AF 3.2.00.38).
PY - 2006/3
Y1 - 2006/3
N2 - 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 α gene (ESR1) 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 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. 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 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.
AB - 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 α gene (ESR1) 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 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. 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 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.
KW - Airway hyperresponsiveness
KW - Asthma
KW - Estrogen receptor 1
KW - Gene polymorphism
KW - Lung function decline
KW - Sex
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U2 - 10.1016/j.jaci.2005.11.023
DO - 10.1016/j.jaci.2005.11.023
M3 - Article
C2 - 16522460
AN - SCOPUS:33644781468
SN - 0091-6749
VL - 117
SP - 604
EP - 611
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 3
ER -