Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian Randomisation
<b>Objectives</b>: Thyroid dysfunction, particularly hypothyroidism, has been associated with endometrial cancer in observational studies; however, these findings may be confounded by obesity, an endometrial cancer risk factor. To clarify these associations, we performed Mendelian random...
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2025-07-01
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| author | Dylan M. Glubb Xuemin Wang Tracy A. O’Mara |
| author_facet | Dylan M. Glubb Xuemin Wang Tracy A. O’Mara |
| author_sort | Dylan M. Glubb |
| collection | DOAJ |
| description | <b>Objectives</b>: Thyroid dysfunction, particularly hypothyroidism, has been associated with endometrial cancer in observational studies; however, these findings may be confounded by obesity, an endometrial cancer risk factor. To clarify these associations, we performed Mendelian randomisation analysis, a genetic approach that mitigates confounding and reverse causation analyses. <b>Methods</b>: We accessed European-ancestry GWAS summary statistics for endometrial cancer (12,270 cases; 46,126 controls), endometrioid (8758 cases), and non-endometrioid (1230 cases) subtypes. Thyroid dysfunction phenotype and BMI GWAS data were predominantly from individuals of European descent. We used these datasets to conduct univariable and multivariable Mendelian randomisation analyses incorporating body mass index (BMI). <b>Results</b>: Our main finding was a causal association between hypothyroidism and decreased risk of endometrial cancer (OR = 0.93; 95% CI 0.89–0.97; <i>p</i> = 3.96 × 10<sup>−4</sup>). Subtype analysis revealed a decreased risk of the most common histological subtype, endometrioid endometrial cancer, and a similar protective association for Hashimoto’s thyroiditis, an autoimmune disease and common cause of hypothyroidism. Sensitivity analyses confirmed the robustness of the associations. Further analyses revealed that while BMI was causally associated with hypothyroidism risk, both BMI and hypothyroidism independently influenced endometrial cancer risk. <b>Conclusions</b>: Our study has identified hypothyroidism as a protective factor for endometrial cancer, challenging previous observational associations and highlighting potential confounding by obesity. Further investigation into immune mechanisms, particularly those linked to Hashimoto’s thyroiditis, may provide insights into the biological pathways underlying endometrial cancer development. |
| format | Article |
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| institution | Matheson Library |
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| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-ab51bb8d2f39458bb39c75c8d6f30c8b2025-07-25T13:15:57ZengMDPI AGBiomedicines2227-90592025-07-01137172910.3390/biomedicines13071729Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian RandomisationDylan M. Glubb0Xuemin Wang1Tracy A. O’Mara2Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, AustraliaCancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, AustraliaCancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia<b>Objectives</b>: Thyroid dysfunction, particularly hypothyroidism, has been associated with endometrial cancer in observational studies; however, these findings may be confounded by obesity, an endometrial cancer risk factor. To clarify these associations, we performed Mendelian randomisation analysis, a genetic approach that mitigates confounding and reverse causation analyses. <b>Methods</b>: We accessed European-ancestry GWAS summary statistics for endometrial cancer (12,270 cases; 46,126 controls), endometrioid (8758 cases), and non-endometrioid (1230 cases) subtypes. Thyroid dysfunction phenotype and BMI GWAS data were predominantly from individuals of European descent. We used these datasets to conduct univariable and multivariable Mendelian randomisation analyses incorporating body mass index (BMI). <b>Results</b>: Our main finding was a causal association between hypothyroidism and decreased risk of endometrial cancer (OR = 0.93; 95% CI 0.89–0.97; <i>p</i> = 3.96 × 10<sup>−4</sup>). Subtype analysis revealed a decreased risk of the most common histological subtype, endometrioid endometrial cancer, and a similar protective association for Hashimoto’s thyroiditis, an autoimmune disease and common cause of hypothyroidism. Sensitivity analyses confirmed the robustness of the associations. Further analyses revealed that while BMI was causally associated with hypothyroidism risk, both BMI and hypothyroidism independently influenced endometrial cancer risk. <b>Conclusions</b>: Our study has identified hypothyroidism as a protective factor for endometrial cancer, challenging previous observational associations and highlighting potential confounding by obesity. Further investigation into immune mechanisms, particularly those linked to Hashimoto’s thyroiditis, may provide insights into the biological pathways underlying endometrial cancer development.https://www.mdpi.com/2227-9059/13/7/1729endometrial cancerthyroid dysfunctionhypothyroidismbody mass indexgenome-wide association studyMendelian randomisation |
| spellingShingle | Dylan M. Glubb Xuemin Wang Tracy A. O’Mara Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian Randomisation Biomedicines endometrial cancer thyroid dysfunction hypothyroidism body mass index genome-wide association study Mendelian randomisation |
| title | Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian Randomisation |
| title_full | Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian Randomisation |
| title_fullStr | Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian Randomisation |
| title_full_unstemmed | Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian Randomisation |
| title_short | Independent Effects of Hypothyroidism and Obesity on Endometrial Cancer Risk Revealed by Mendelian Randomisation |
| title_sort | independent effects of hypothyroidism and obesity on endometrial cancer risk revealed by mendelian randomisation |
| topic | endometrial cancer thyroid dysfunction hypothyroidism body mass index genome-wide association study Mendelian randomisation |
| url | https://www.mdpi.com/2227-9059/13/7/1729 |
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