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Original article
Genetic and observational evidence supports a causal role of sex hormones on the development of asthma
  1. Ryan Arathimos1,2,
  2. Raquel Granell1,
  3. Philip Haycock1,2,
  4. Rebecca C Richmond1,2,
  5. James Yarmolinsky1,2,
  6. Caroline L Relton1,2,
  7. Kate Tilling1,2
  1. 1 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
  2. 2 Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK
  1. Correspondence to Dr Ryan Arathimos, MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK; ryan.arathimos{at}


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.

  • sex hormones
  • cohort
  • asthma
  • testosterone
  • SHBG

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  • Contributors RA, RG, KT and CLR were involved in project conceptualisation. RA and KT performed the formal analysis. RA, RG, RCR, JY and CLR were involved in methodology development. PH was involved in data curation and software provision. RA prepared the original draft. RG, PH, JY, RCR, CLR and KT reviewed and edited the manuscript.

  • Funding This work was supported by the MRC Integrative Epidemiology Unit and the University of Bristol (MC_UU_00011/5 and MC_UU_00011/3). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( This research has been conducted using the UK Biobank Resource under Application No 15825.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Ethical approval for ALSPAC was obtained from the ALSPAC Ethics and Law Committee and the local research ethics committees. UK Biobank received ethical approval from the Research Ethics Committee (REC reference 11/NW/0382).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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