性激素影响哮喘发展的遗传和观察证据
2019/04/19
摘要
介绍：男性在儿童时期的哮喘患病率较高，而女性在青春期和成年期的患病率较高。青春期时性别之间的“青少年转换”被认为是由于性激素的波动。关于性激素参与哮喘的有力证据可能会促进治疗干预的发展。
方法：我们综合了一些纵向数据的观察性证据，包括性激素结合球蛋白（SHBG）、总体和生物可利用睾酮以及父母和儿童Avon纵向研究中的一部分男性哮喘（n = 512）等，以及使用双样本孟德尔随机化（MR），一种因果推断方法，获得的SHBG和哮喘的遗传性证据。我们荟萃分析了两个大型数据集的双样本MR结果，即跨国哮喘遗传学联盟哮喘全基因组关联研究和英国生物库，样本总计超过460,000人。
结果：观察证据表明，青春期男性睾酮增加对哮喘的保护作用证据不充分，但与SHBG没有明显相关。使用双样本MR的遗传证据表明SHBG增加有保护作用，反向方差加权方法的哮喘OR为0.86（95％CI 0.74至1.00），加权中值估计SHBG自然对数的每单位增加OR为0.83（95％CI 0.72至0.96）。性别分层敏感性分析表明SHBG的保护作用在女性中最为明显。
结论：我们报告了第一个提示证据，即SHBG遗传性升高对哮喘具有保护作用，这可能为观察到的哮喘性别不一致提供了生物学解释。需要进一步的工作来研究SHBG对哮喘的下游影响和所涉及的分子途径。
Genetic and observational evidence supports a causal role of sex hormones on the development of asthma.
Arathimos R, Granell R, Haycock P, Richmond RC, Yarmolinsky J, Relton CL, Tilling K.
Abstract
INTRODUCTION:Males have a higher prevalence of asthma in childhood, whereas females have a higher prevalence in adolescence and adulthood. The 'adolescent switch' observed between sexes during puberty has been hypothesised to be due to fluctuating sex hormones. Robust evidence of the involvement of sex hormones in asthma could lead to development of therapeutic interventions.
METHODS:We combine observational evidence using longitudinal data on sex hormone-binding globulin (SHBG), total and bioavailable testosterone and asthma from a subset of males (n=512) in the Avon Longitudinal Study of Parents and Children, and genetic evidence of SHBG and asthma using two-sample Mendelian randomisation (MR), a method of causal inference. We meta-analysed two-sample MR results across two large data sets, the Trans-National Asthma Genetics Consortium genome-wide association study of asthma and UK Biobank (over 460 000 individuals combined).
RESULTS:Observational evidence indicated weak evidence of a protective effect of increased circulating testosterone on asthma in males in adolescence, but no strong pattern of association with SHBG. Genetic evidence using two-sample MR indicated a protective effect of increased SHBG, with an OR for asthma of 0.86 (95% CI 0.74 to 1.00) for the inverse-variance weighted approach and an OR of 0.83 (95% CI 0.72 to 0.96) for the weighted median estimator, per unit increase in natural log SHBG. A sex-stratified sensitivity analysis suggested the protective effect of SHBG was mostly evident in females.
CONCLUSION:We report the first suggestive evidence of a protective effect of genetically elevated SHBG on asthma, which may provide a biological explanation behind the observed asthma sex discordance. Further work is required to disentangle the downstream effects of SHBG on asthma and the molecular pathways involved.
介绍：男性在儿童时期的哮喘患病率较高，而女性在青春期和成年期的患病率较高。青春期时性别之间的“青少年转换”被认为是由于性激素的波动。关于性激素参与哮喘的有力证据可能会促进治疗干预的发展。
方法：我们综合了一些纵向数据的观察性证据，包括性激素结合球蛋白（SHBG）、总体和生物可利用睾酮以及父母和儿童Avon纵向研究中的一部分男性哮喘（n = 512）等，以及使用双样本孟德尔随机化（MR），一种因果推断方法，获得的SHBG和哮喘的遗传性证据。我们荟萃分析了两个大型数据集的双样本MR结果，即跨国哮喘遗传学联盟哮喘全基因组关联研究和英国生物库，样本总计超过460,000人。
结果：观察证据表明，青春期男性睾酮增加对哮喘的保护作用证据不充分，但与SHBG没有明显相关。使用双样本MR的遗传证据表明SHBG增加有保护作用，反向方差加权方法的哮喘OR为0.86（95％CI 0.74至1.00），加权中值估计SHBG自然对数的每单位增加OR为0.83（95％CI 0.72至0.96）。性别分层敏感性分析表明SHBG的保护作用在女性中最为明显。
结论：我们报告了第一个提示证据，即SHBG遗传性升高对哮喘具有保护作用，这可能为观察到的哮喘性别不一致提供了生物学解释。需要进一步的工作来研究SHBG对哮喘的下游影响和所涉及的分子途径。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Thorax. 2019 Apr 1. pii: thoraxjnl-2018-212207. doi: 10.1136/thoraxjnl-2018-212207.)
(Thorax. 2019 Apr 1. pii: thoraxjnl-2018-212207. doi: 10.1136/thoraxjnl-2018-212207.)
Genetic and observational evidence supports a causal role of sex hormones on the development of asthma.
Arathimos R, Granell R, Haycock P, Richmond RC, Yarmolinsky J, Relton CL, Tilling K.
Abstract
INTRODUCTION:Males have a higher prevalence of asthma in childhood, whereas females have a higher prevalence in adolescence and adulthood. The 'adolescent switch' observed between sexes during puberty has been hypothesised to be due to fluctuating sex hormones. Robust evidence of the involvement of sex hormones in asthma could lead to development of therapeutic interventions.
METHODS:We combine observational evidence using longitudinal data on sex hormone-binding globulin (SHBG), total and bioavailable testosterone and asthma from a subset of males (n=512) in the Avon Longitudinal Study of Parents and Children, and genetic evidence of SHBG and asthma using two-sample Mendelian randomisation (MR), a method of causal inference. We meta-analysed two-sample MR results across two large data sets, the Trans-National Asthma Genetics Consortium genome-wide association study of asthma and UK Biobank (over 460 000 individuals combined).
RESULTS:Observational evidence indicated weak evidence of a protective effect of increased circulating testosterone on asthma in males in adolescence, but no strong pattern of association with SHBG. Genetic evidence using two-sample MR indicated a protective effect of increased SHBG, with an OR for asthma of 0.86 (95% CI 0.74 to 1.00) for the inverse-variance weighted approach and an OR of 0.83 (95% CI 0.72 to 0.96) for the weighted median estimator, per unit increase in natural log SHBG. A sex-stratified sensitivity analysis suggested the protective effect of SHBG was mostly evident in females.
CONCLUSION:We report the first suggestive evidence of a protective effect of genetically elevated SHBG on asthma, which may provide a biological explanation behind the observed asthma sex discordance. Further work is required to disentangle the downstream effects of SHBG on asthma and the molecular pathways involved.
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