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Sex hormone binding globulin and risk of breast cancer: a Mendelian randomization study

Research output: Contribution to journalArticle

Original languageEnglish
Number of pages10
JournalInternational Journal of Epidemiology
Early online date29 May 2019
DOIs
DateAccepted/In press - 2 May 2019
DateE-pub ahead of print (current) - 29 May 2019

Abstract

Background: There are observational data suggesting an inverse association between circulating concentrations of sex hormone binding globulin (SHBG) and risk of postmenopausal breast cancer. However, causality is uncertain and few studies have investigated this association by tumour receptor status. We aimed to investigate these associations under the causal framework of Mendelian randomization (MR).

Methods: We used summary association estimates extracted from published genome-wide association study (GWAS) meta-analyses for SHBG and breast cancer to perform two-sample MR analyses. Summary statistics were available for 122,977 overall breast cancer cases, of which 69,501 were estrogen receptor positive (ER+ve) and 21,468 were ER-ve, and 105,974 controls. To control for potential horizontal pleiotropy acting via body mass index (BMI), we performed multivariable inverse-variance weighted (IVW) MR as the main analysis with the robustness of this approach further tested in sensitivity analyses.

Results: The multivariable IVW MR analysis indicated a lower risk of overall (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.90, 0.98; P: 0.006) and ER+ve (OR: 0.92; 95% CI: 0.87, 0.97; P: 0.003) breast cancer, and a higher risk of ER-ve disease (OR: 1.09; 95% CI: 1.00, 1.18; P: 0.047) per 25 nmol/L higher SHBG levels. Sensitivity analyses were consistent with the findings of the main analysis.

Conclusions: We corroborated the previous literature evidence coming from observational studies for a potentially causal inverse association between SHBG concentrations and risk of ER+ve breast cancer, but our findings also suggested a potential novel positive association with ER-ve disease that warrants further investigation given the low prior probability of being true.

    Research areas

  • Sex hormone binding globulin, breast cancer, Mendelian randomization

    Structured keywords

  • ICEP

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Documents

  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Oxford University Press at https://academic.oup.com/ije/advance-article/doi/10.1093/ije/dyz107/5506081 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 314 KB, PDF-document

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  • Supplementary information PDF Tables

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  • Supplementary information PDF Supplementary Tables

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  • Supplementary information TIFF Figure 1

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  • Supplementary information TIFF Figure 2

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