Association between Thyrotoxicosis and Gestational Diabetes Mellitus: A Mendelian Randomization Study
Abstract
Background: Insulin resistance and abnormal glucose metabolism are the main characteristics of thyrotoxicosis and gestational diabetes mellitus (GDM). However, it remains unclear whether thyrotoxicosis increases the risk of GDM. Therefore, this research aimed to explore the causality between thyrotoxicosis and GDM by using a Mendelian randomization (MR) analysis.
Methods: A MR analysis was conducted to explore the causal effects of thyrotoxicosis on GDM. Summary statistics data of thyrotoxicosis (3115 thyrotoxicosis cases and 187684 controls) and GDM (13039 cases and 197831 controls) were derived from genome-wide association study. We selected MR Egger, Weighted median, Inverse-variance weighted, Simple mode and Weighted mode to evaluate the causal effect between thyrotoxicosis and GDM.
Results: By using a two-sample MR analysis, we found a strong causal relationship between thyrotoxicosis and GDM as indicated by Inverse-variance weighted (OR=1.069; beta=0.067; 95%CI=1.023-1.118; P=0.003), Weighted median (OR=1.087; beta=0.084; 95%CI=1.040-1.137; P=0.0002), Simple mode (OR=1.102; beta=0.097; 95%CI= 1.038-1.170; P=0.013) and Weighted mode (OR=1.089; beta=0.085; 95%CI=1.033-1.147; P=0.013). No significant pleiotropy, heterogeneity, genetic correlations or bi-directional causal relationship was existed in this study. Bayesian colocalization suggested that thyrotoxicosis colocalized with GDM on rs10830963 (PP.H4 = 1.000), where rs10830963 was located on MTNR1B gene locus.
Conclusion: Thyrotoxicosis had a causal effect on the risk of developing GDM, and the exposure of thyrotoxicosis increased the risk of GDM.
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18. Rezzonico J, Niepomniszcze H, Rezzonico M, et al (2011). The association of insulin resistance with subclinical thyrotoxicosis. Thyroid, 21(9):945-9.
19. Pestell R, Alford F, Ramos R, et al (1990). Insulin secretion, insulin sensitivity and glucose-mediated glucose disposal in thyrotoxicosis: a minimal model analysis. Clin Endocrinol (Oxf), 33(4):481-93.
20. Saunders J, Hall SE, Sönksen PH (1980). Glucose and free fatty acid turnover in thyrotoxicosis and hypothyroidism, before and after treatment. Clin Endocrinol (Oxf), 13(1):33-44.
21. Tudela CM, Casey BM, McIntire DD, et al (2012). Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol, 119(5):983-8.
22. Stohl HE, Ouzounian J, Rick AM, et al (2013). Thyroid disease and gestational diabetes mellitus (GDM): is there a connection? J Matern Fetal Neonatal Med, 26(11):1139-42.
23. Skrivankova VW, Richmond RC, Woolf BAR, et al (2021). Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA, 326(16):1614-1621.
24. Kurki MI, Karjalainen J, Palta P, et al (2023). FinnGen provides genetic insights from a well-phenotyped isolated population. Nature, 613(7944):508-518.
25. Zhang J, Zhou C, Guan S (2024). Association Between Rheumatoid Arthritis and Clonal Hematopoiesis: A Mendelian Randomization Study. Twin Res Hum Genet: 27(3):169-173.
26. Karakosta P, Alegakis D, Georgiou V, et al (2012). Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab, 97(12):4464-72.
27. Kumru P, Erdogdu E, Arisoy R, et al (2015). Effect of thyroid dysfunction and autoimmunity on pregnancy outcomes in low risk population. Arch Gynecol Obstet, 291(5):1047-54.
28. Wikner BN, Sparre LS, Stiller CO, et al (2008). Maternal use of thyroid hormones in pregnancy and neonatal outcome. Acta Obstet Gynecol Scand, 87(6):617-27.
29. Mason IC, Qian J, Adler GK, et al (2020). Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes. Diabetologia, 63(3):462-472.
30. Garaulet M, Lopez-Minguez J, Dashti HS, et al (2022). Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial. Diabetes Care, 45(3):512-519.
31. Liang Z, Liu H, Wang L, et al(2020). Maternal MTNR1B genotype, maternal gestational weight gain, and childhood obesity. Am J Clin Nutr, 111(2):360-368.
32. Bai Y, Tang L, Li L, et al (2020). The roles of ADIPOQ rs266729 and MTNR1B rs10830963 polymorphisms in patients with gestational diabetes mellitus: A meta-analysis. Gene, 730:144302.
33. Firneisz G, Rosta K, Al-Aissa Z, et al (2018). The MTNR1B rs10830963 Variant in Interaction with Pre-Pregnancy BMI is a Pharmacogenetic Marker for the Initiation of Antenatal Insulin Therapy in Gestational Diabetes Mellitus. Int J Mol Sci, 19(12):3734.
34. Sewerynek E, Wiktorska J, Lewinski A (1999). Effects of melatonin on the oxidative stress induced by thyrotoxicosis in rats. Neuro Endocrinol Lett, 20(3-4):157-161.
35. Lin JD, Fang WF, Tang KT, et al (2019). Effects of exogenous melatonin on clinical and pathological features of a human thyroglobulin-induced experimental autoimmune thyroiditis mouse model. Sci Rep, 9(1):5886.
2. Sacks DA, Hadden DR, Maresh M, et al (2012). Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care, 35(3):526-8.
3. Zhu Y, Zhang C (2016). Prevalence of Gestational Diabetes and Risk of Progression to Type 2 Diabetes: a Global Perspective. Curr Diab Rep, 16(1):7.
4. Sweeting A, Wong J, Murphy HR, et al (2022). A Clinical Update on Gestational Diabetes Mellitus. Endocr Rev, 43(5):763-793.
5. McIntyre HD, Catalano P, Zhang C, et al (2019). Gestational diabetes mellitus. Nat Rev Dis Primers, 5(1):47.
6. Coustan DR (2013). Gestational diabetes mellitus. Clin Chem, 59(9):1310-1321.
7. Ye W, Luo C, Huang J, et al (2022). Gestational diabetes mellitus and adverse pregnancy outcomes: systematic review and meta-analysis. BMJ, 377:e067946.
8. Bellamy L, Casas JP, Hingorani AD, et al (2009). Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet, 373(9677):1773-9.
9. Kim C, Berger DK, Chamany S (2007). Recurrence of gestational diabetes mellitus: a systematic review. Diabetes Care, 30(5):1314-9.
10. Cleary-Goldman J, Malone FD, Vidaver J, et al (2005). Impact of maternal age on obstetric outcome. Obstet Gynecol, 105(5 Pt 1):983-90.
11. Morisset AS, St-Yves A, Veillette J, et al (2010). Prevention of gestational diabetes mellitus: a review of studies on weight management. Diabetes Metab Res Rev, 26(1):17-25.
12. Petry CJ (2010). Gestational diabetes: risk factors and recent advances in its genetics and treatment. Br J Nutr, 104(6):775-87.
13. De Leo S, Lee SY, Braverman LE (2016). Hyperthyroidism. Lancet, 388(10047):906-918.
14. Golden SH, Robinson KA, Saldanha I, et al (2009). Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab, 94(6):1853-78.
15. Sawin CT, Geller A, Wolf PA, et al (1994). Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med, 331(19):1249-52.
16. Abe E, Marians RC, Yu W, et al (2003). TSH is a negative regulator of skeletal remodeling. Cell, 115(2):151-62.
17. Kalra S, Aggarwal S, Khandelwal D (2019). Thyroid Dysfunction and Type 2 Diabetes Mellitus: Screening Strategies and Implications for Management. Diabetes Ther, 10(6):2035-2044.
18. Rezzonico J, Niepomniszcze H, Rezzonico M, et al (2011). The association of insulin resistance with subclinical thyrotoxicosis. Thyroid, 21(9):945-9.
19. Pestell R, Alford F, Ramos R, et al (1990). Insulin secretion, insulin sensitivity and glucose-mediated glucose disposal in thyrotoxicosis: a minimal model analysis. Clin Endocrinol (Oxf), 33(4):481-93.
20. Saunders J, Hall SE, Sönksen PH (1980). Glucose and free fatty acid turnover in thyrotoxicosis and hypothyroidism, before and after treatment. Clin Endocrinol (Oxf), 13(1):33-44.
21. Tudela CM, Casey BM, McIntire DD, et al (2012). Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol, 119(5):983-8.
22. Stohl HE, Ouzounian J, Rick AM, et al (2013). Thyroid disease and gestational diabetes mellitus (GDM): is there a connection? J Matern Fetal Neonatal Med, 26(11):1139-42.
23. Skrivankova VW, Richmond RC, Woolf BAR, et al (2021). Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA, 326(16):1614-1621.
24. Kurki MI, Karjalainen J, Palta P, et al (2023). FinnGen provides genetic insights from a well-phenotyped isolated population. Nature, 613(7944):508-518.
25. Zhang J, Zhou C, Guan S (2024). Association Between Rheumatoid Arthritis and Clonal Hematopoiesis: A Mendelian Randomization Study. Twin Res Hum Genet: 27(3):169-173.
26. Karakosta P, Alegakis D, Georgiou V, et al (2012). Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab, 97(12):4464-72.
27. Kumru P, Erdogdu E, Arisoy R, et al (2015). Effect of thyroid dysfunction and autoimmunity on pregnancy outcomes in low risk population. Arch Gynecol Obstet, 291(5):1047-54.
28. Wikner BN, Sparre LS, Stiller CO, et al (2008). Maternal use of thyroid hormones in pregnancy and neonatal outcome. Acta Obstet Gynecol Scand, 87(6):617-27.
29. Mason IC, Qian J, Adler GK, et al (2020). Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes. Diabetologia, 63(3):462-472.
30. Garaulet M, Lopez-Minguez J, Dashti HS, et al (2022). Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial. Diabetes Care, 45(3):512-519.
31. Liang Z, Liu H, Wang L, et al(2020). Maternal MTNR1B genotype, maternal gestational weight gain, and childhood obesity. Am J Clin Nutr, 111(2):360-368.
32. Bai Y, Tang L, Li L, et al (2020). The roles of ADIPOQ rs266729 and MTNR1B rs10830963 polymorphisms in patients with gestational diabetes mellitus: A meta-analysis. Gene, 730:144302.
33. Firneisz G, Rosta K, Al-Aissa Z, et al (2018). The MTNR1B rs10830963 Variant in Interaction with Pre-Pregnancy BMI is a Pharmacogenetic Marker for the Initiation of Antenatal Insulin Therapy in Gestational Diabetes Mellitus. Int J Mol Sci, 19(12):3734.
34. Sewerynek E, Wiktorska J, Lewinski A (1999). Effects of melatonin on the oxidative stress induced by thyrotoxicosis in rats. Neuro Endocrinol Lett, 20(3-4):157-161.
35. Lin JD, Fang WF, Tang KT, et al (2019). Effects of exogenous melatonin on clinical and pathological features of a human thyroglobulin-induced experimental autoimmune thyroiditis mouse model. Sci Rep, 9(1):5886.
| Files | ||
| Issue | Vol 54 No 8 (2025) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v54i8.19580 | |
| Keywords | ||
| Mendelian randomization Gestational diabetes mellitus Thyrotoxicosis Insulin resistance | ||
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How to Cite
1.
Chen Y, Guan S, Su X, Zhuang W. Association between Thyrotoxicosis and Gestational Diabetes Mellitus: A Mendelian Randomization Study. Iran J Public Health. 2025;54(8):1712-1720.
