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Respiratory epidemiology
Original research
Effects of testosterone and sex hormone binding globulin on lung function in males and females: a multivariable Mendelian Randomisation study
  1. Diana A van der Plaat1,
  2. Alexandra Lenoir2,3,
  3. Shyamali Dharmage4,
  4. James Potts1,
  5. Francisco Gómez Real5,6,
  6. Seif O Shaheen7,
  7. Debbie Jarvis1,
  8. Cosetta Minelli1,
  9. Bénédicte Leynaert8
  1. 1National Heart and Lung Institute (NHLI), Imperial College London, London, UK
  2. 2Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  3. 3Gesundheitsamt Fürstenfeldbruck, Fürstenfeldbruck, Switzerland
  4. 4Allergy and Lung Health Unit, The University of Melbourne School of Population and Global Health, Melbourne, Victoria, Australia
  5. 5Department of Clinical Science, University of Bergen, Bergen, Norway
  6. 6Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
  7. 7Wolfson Institute of Population Health, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, London, UK
  8. 8Université Paris-Saclay, UVSQ, Université Paris-Sud, Inserm, Équipe d'Épidémiologie Respiratoire Intégrative, CESP, INSERM, Villejuif, France
  1. Correspondence to Dr Diana A van der Plaat, National Heart and Lung Institute (NHLI), Imperial College London, London, UK; d.van-der-plaat{at}imperial.ac.uk

Abstract

Background Observational studies suggest that total testosterone (TT) and sex hormone-binding globulin (SHBG) may have beneficial effects on lung function, but these findings might be spurious due to confounding and reverse causation. We addressed these limitations by using multivariable Mendelian randomisation (MVMR) to investigate the independent causal effects of TT and SHBG on lung function.

Methods We first identified genetic instruments by performing genome-wide association analyses of TT and SHBG in the large UK Biobank, separately in males and females. We then assessed the independent effects of TT and SHBG on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using one-sample MVMR. We addressed pleiotropy, which could bias MVMR, using several methods that account for it. We performed subgroup MVMR analyses by obesity, physical activity and menopausal status, and assessed associations between TT and SHBG with lung function decline. Finally, we compared the MVMR results with those of observational analyses in the UK Biobank.

Findings In the MVMR analyses, there was evidence of pleiotropy, but results were consistent when accounting for it. We found a strong beneficial effect of TT on FVC and FEV1 in both males and females, but a moderate detrimental effect of SHBG on FEV1 and FEV1/FVC in males only. Subgroup analyses suggested stronger effects of TT among obese and older males. The observational analyses, in line with previous studies, agreed with MRMV for TT, but not for SHBG.

Interpretation These findings suggest that testosterone improves lung function in males and females, while SHBG has an opposite independent effect in males.

  • Respiratory Measurement
  • COPD epidemiology

Data availability statement

All data relevant to perform the multivariable Mendelian randomisation analyses are included as online supplemental information (G-X and G-Y in online supplemental table S2). Individual participant data may be obtained from a third party and are not publicly available. Please consult the data access policy of the UK Biobank at https://www.ukbiobank.ac.uk/.

https://doi.org/10.1136/thorax-2023-220374

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    Data availability statement

    All data relevant to perform the multivariable Mendelian randomisation analyses are included as online supplemental information (G-X and G-Y in online supplemental table S2). Individual participant data may be obtained from a third party and are not publicly available. Please consult the data access policy of the UK Biobank at https://www.ukbiobank.ac.uk/.

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    Footnotes

    • CM and BL are joint senior authors.

    • Correction notice This article has been corrected since it was published Online First. A typo in the title has been fixed.

    • Contributors DAvdP participated in the study design, analysis and interpretation of the data, and drafting of the manuscript, tables and figures, and is guarantor of the work. CM, BL and DAvdP participated in determining the study design and interpretation of the data. CM, BL, AL, SD, JP, FGR and DJ were involved in data collection and interpretation of the data. SOS, BL, CM, DJ, SD and FGR obtained funding. All authors read and approved the final version of the manuscript.

    • Funding The current study is part of the Ageing for Lungs in European Cohorts (ALEC) study (www.alecstudy.org), which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 633212. This research has been conducted using the UK Biobank Resource under application number 19136, and we thank the participants, field workers and data managers for their time and cooperation. This work used the computing resources of the UK Medical Bionformatics partnership—aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO) which is supported by the Medical Research Council (grant number MR/L01632X/1).

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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