Vitamin D, obesity and polycystic ovary syndrome: a two-sample and multivariate Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

WEN Weian ¹ ,  SONG Ning ¹ , LI Jingxia ² , DING Yuesen ²

1. Zhuang Medical School of Clinical Medicine, Guangxi University of Traditional Chinese Medicine, Nanning 530000, P. R. China;
2. Acupuncture Rehabilitation Department, Guangzhou City Conghua District Hospital of Chinese Medicine, Guangzhou 510000, P. R. China;

Corresponding author：

SONG Ning, Email: gxsn1016@126.com

Keywords：

Vitamin D; Polycystic ovary syndrome; Mendelian randomization; Multivariate

DOI：

10.7507/1672-2531.202407068

Video：

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Objective To evaluate the association between vitamin D levels and polycystic ovarian syndrome (PCOS) by Mendelian randomization (MR) analysis, and assessed the role of obesity in this association. Methods Public genome-wide association studies were used to obtain single nucleotide polymorphism (SNP) data of exposure and outcome. Inverse variance weighting (IVW) was used as the main analysis method to analyze the causal relationship between vitamin D level (including total vitamin D level, serum 25-hydroxyvitamin D level) and vitamin D-binding protein level and polycystic ovary syndrome. In addition, multivariate MR method was used to explore the influence of obesity. Results IVW method showed that 25-hydroxyvitamin D was a protective factor for PCOS (OR=0.185, 95%CI 0.058 to 0.585, P=0.004). There was no interference of heterogeneity and horizontal pleiotropy among the data, and the data tended to be stable in general. The remaining total vitamin D levels and vitamin D-binding protein levels did not show an association with PCOS at the genetic level. MVMR analysis adjusted for obesity and BMI in adolescents showed that 25-hydroxyvitamin D was still negatively associated with the risk of PCOS (OR=3.354, 95%CI 0.150 to 2.270, P=0.025). Conclusion By bidirectional Mendelian randomization analysis, serum 25-hydroxyvitamin D is identified as a protective factor for PCOS, and the increase of serum 25-hydroxyvitamin D level can reduce the risk of PCOS. Obesity does not affect the causal relationship between serum 25-hydroxyvitamin D and PCOS at the genetic level.

1.	Piltonen TT, Arffman RK, Joham AE. Natural history of polycystic ovary syndrome and new advances in the epidemiology. Semin Reprod Med, 2021, 39(3-04): 94-101.
2.	Yang R, Li Q, Zhou Z, et al. Changes in the prevalence of polycystic ovary syndrome in China over the past decade. Lancet Reg Health West Pac, 2022, 25: 100494.
3.	薛诗瑶, 杨刚毅. 多囊卵巢综合征的诊治进展. 中华内分泌代谢杂志, 2020, 36(1): 88-92.
4.	Gao L, Zhao Y, Wu H, et al. Polycystic ovary syndrome fuels cardiovascular inflammation and aggravates ischemic cardiac injury. Circulation, 2023, 148(24): 1958-1973.
5.	范祖莉, CholekhoSumita, 谭惠文. 2023年《多囊卵巢综合征评估和管理建议的国际循证指南》解读. 成都医学院学报, 2023, 18(6): 681-685.
6.	He C, Lin Z, Robb SW, et al. Serum vitamin D levels and polycystic ovary syndrome: a systematic review and meta-analysis. Nutrients, 2015, 7(6): 4555-4577.
7.	Yang M, Shen X, Lu D, et al. Effects of vitamin D supplementation on ovulation and pregnancy in women with polycystic ovary syndrome: a systematic review and meta-analysis. Front Endocrinol (Lausanne), 2023, 14: 1148556.
8.	Sert ZS, Yılmaz SA, Seçilmiş Ö, et al. Effect of calcium and vitamin D supplementation on the clinical, hormonal, and metabolic profile in non-obese women with polycystic ovary syndrome. Ir J Med Sci, 2022, 191(6): 2657-2662.
9.	Al-Bayyari N, Al-Domi H, Zayed F, et al. Androgens and hirsutism score of overweight women with polycystic ovary syndrome improved after vitamin D treatment: a randomized placebo controlled clinical trial. Clin Nutr, 2021, 40(3): 870-878.
10.	Kuyucu Y, Sencar L, Tap Ö, et al. Investigation of the effects of vitamin D treatment on the ovarian AMH receptors in a polycystic ovary syndrome experimental model: an ultrastructural and immunohistochemical study. Reprod Biol, 2020, 20(1): 25-32.
11.	Azhar A, Haider G, Naseem Z, et al. Morphological changes in the experimental model of polycystic ovary syndrome and effects of vitamin D treatment. J Obstet Gynaecol Res, 2021, 47(3): 1164-1171.
12.	孟欣, 李娜, 曹浩哲, 等. VDBP基因多态性及血清维生素D水平与多囊卵巢综合征代谢紊乱的相关性. 中国优生与遗传杂志, 2023, 31(12): 2465-2471.
13.	Yildizhan R, Kurdoglu M, Adali E, et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet, 2009, 280(4): 559-563.
14.	Moin ASM, Sathyapalan T, Atkin SL, et al. Inflammatory markers in non-obese women with polycystic ovary syndrome are not elevated and show no correlation with vitamin D metabolites. Nutrients, 2022, 14(17): 3540.
15.	Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
16.	Ference BA, Holmes MV, Smith GD. Using Mendelian randomization to improve the design of randomized trials. Cold Spring Harb Perspect Med, 2021, 11(7): a040980.
17.	Qi L. Mendelian randomization in nutritional epidemiology. Nutr Rev, 2009, 67(8): 439-450.
18.	Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: a review. Res Synth Methods, 2019, 10(4): 486-496.
19.	Sanderson E. Multivariable Mendelian randomization and mediation. Cold Spring Harb Perspect Med, 2021, 11(2): a038984.
20.	Várbíró S, Takács I, Tűű L, et al. Effects of vitamin D on fertility, pregnancy and polycystic ovary syndrome-a review. Nutrients, 2022, 14(8): 1649.
21.	Dastorani M, Aghadavod E, Mirhosseini N, et al. The effects of vitamin D supplementation on metabolic profiles and gene expression of insulin and lipid metabolism in infertile polycystic ovary syndrome candidates for in vitro fertilization. Reprod Biol Endocrinol, 2018, 16(1): 94.
22.	柳雨雨, 袁涛, 李海鸿, 等. 维生素D治疗多囊卵巢综合征有效性的Meta分析. 中国循证医学杂志, 2020, 20(6): 695-701.
23.	杨婷, 陈琳, 程薇, 等. 多囊卵巢综合征肥胖患者血清维生素D、铁蛋白水平、sICAM-1与胰岛素抵抗、糖脂代谢指标的相关性. 现代生物医学进展, 2022, 22(12): 2318-2321,2327.
24.	朱晓霞, 夏朋滨, 何亚琼. 补充维生素D联合益生菌对多囊卵巢综合征患者肠道菌群多样性、代谢和激素水平的影响. 中国微生态学杂志, 2020, 32(3): 317-321.
25.	贾新转, 魏兰, 甄秀丽. 维生素D联合二甲双胍及中药对PCOS患者内分泌代谢紊乱的治疗作用分析. 时珍国医国药, 2014, 25(6): 1415-1417.
26.	Ostadmohammadi V, Jamilian M, Bahmani F, et al. Vitamin D and probiotic co-supplementation affects mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome. J Ovarian Res, 2019, 12(1): 5.
27.	Ağar M, Güngör K, Güngör ND, et al. Vitamin D supplementation inhibits NF-kß signaling pathway in lean and obese women with PCOS. Eur Rev Med Pharmacol Sci, 2022, 26(11): 3973-3977.
28.	周加敏, 吴婷婷, 陈琳, 等. 维生素D缺乏与多囊卵巢综合征发病机制的相关性研究. 南京医科大学学报(自然科学版), 2023, 43(7): 934-944.
29.	Gao B, Zhang C, Wang D, et al. Causal association between low vitamin D and polycystic ovary syndrome: a bidirectional mendelian randomization study. J Ovarian Res, 2024, 17(1): 95.
30.	Contreras-Bolívar V, García-Fontana B, García-Fontana C, et al. Mechanisms involved in the relationship between vitamin D and insulin resistance: impact on clinical practice. Nutrients, 2021, 13(10): 3491.
31.	Merhi Z. Crosstalk between advanced glycation end products and vitamin D: a compelling paradigm for the treatment of ovarian dysfunction in PCOS. Mol Cell Endocrinol, 2019, 479: 20-26.
32.	Nowak A, Wojtowicz M, Baranski K, et al. The correlation of vitamin D level with body mass index in women with PCOS. Ginekol Pol, 2023, 94(11): 883-888.
33.	Dokuzeylül Güngör N, Güngör K, Celik N, et al. Impact of body mass index and vitamin D on serum AMH levels and antral follicle count in PCOS. Eur Rev Med Pharmacol Sci, 2023, 27(1): 179-187.
34.	Saglam Z, Bakir V L, Atas M N, et al. Role of VDR gene polymorphisms and vitamin D levels in normal and overweight patients with PCOS. J Genet, 2024, 103: 7.
35.	Shi XY, Huang AP, Xie DW, et al. Association of vitamin D receptor gene variants with polycystic ovary syndrome: a meta-analysis. BMC Med Genet, 2019, 20(1): 32.
36.	Nestler J E, Reilly E R, Cheang K I, et al. A pilot study: effects of decreasing serum insulin with diazoxide on vitamin D levels in obese women with polycystic ovary syndrome. Trans Am Clin Climatol Assoc, 2012, 123: 209-219.
37.	Eftekhar M, Mirhashemi ES, Molaei B, et al. Is there any association between vitamin D levels and polycystic ovary syndrome (PCOS) phenotypes. Arch Endocrinol Metab, 2020, 64(1): 11-16.
38.	Davis EM, Peck JD, Hansen KR, et al. Associations between vitamin D levels and polycystic ovary syndrome phenotypes. Minerva Endocrinol, 2019, 44(2): 176-184.

1. Piltonen TT, Arffman RK, Joham AE. Natural history of polycystic ovary syndrome and new advances in the epidemiology. Semin Reprod Med, 2021, 39(3-04): 94-101.
2. Yang R, Li Q, Zhou Z, et al. Changes in the prevalence of polycystic ovary syndrome in China over the past decade. Lancet Reg Health West Pac, 2022, 25: 100494.
3. 薛诗瑶, 杨刚毅. 多囊卵巢综合征的诊治进展. 中华内分泌代谢杂志, 2020, 36(1): 88-92.
4. Gao L, Zhao Y, Wu H, et al. Polycystic ovary syndrome fuels cardiovascular inflammation and aggravates ischemic cardiac injury. Circulation, 2023, 148(24): 1958-1973.
5. 范祖莉, CholekhoSumita, 谭惠文. 2023年《多囊卵巢综合征评估和管理建议的国际循证指南》解读. 成都医学院学报, 2023, 18(6): 681-685.
6. He C, Lin Z, Robb SW, et al. Serum vitamin D levels and polycystic ovary syndrome: a systematic review and meta-analysis. Nutrients, 2015, 7(6): 4555-4577.
7. Yang M, Shen X, Lu D, et al. Effects of vitamin D supplementation on ovulation and pregnancy in women with polycystic ovary syndrome: a systematic review and meta-analysis. Front Endocrinol (Lausanne), 2023, 14: 1148556.
8. Sert ZS, Yılmaz SA, Seçilmiş Ö, et al. Effect of calcium and vitamin D supplementation on the clinical, hormonal, and metabolic profile in non-obese women with polycystic ovary syndrome. Ir J Med Sci, 2022, 191(6): 2657-2662.
9. Al-Bayyari N, Al-Domi H, Zayed F, et al. Androgens and hirsutism score of overweight women with polycystic ovary syndrome improved after vitamin D treatment: a randomized placebo controlled clinical trial. Clin Nutr, 2021, 40(3): 870-878.
10. Kuyucu Y, Sencar L, Tap Ö, et al. Investigation of the effects of vitamin D treatment on the ovarian AMH receptors in a polycystic ovary syndrome experimental model: an ultrastructural and immunohistochemical study. Reprod Biol, 2020, 20(1): 25-32.
11. Azhar A, Haider G, Naseem Z, et al. Morphological changes in the experimental model of polycystic ovary syndrome and effects of vitamin D treatment. J Obstet Gynaecol Res, 2021, 47(3): 1164-1171.
12. 孟欣, 李娜, 曹浩哲, 等. VDBP基因多态性及血清维生素D水平与多囊卵巢综合征代谢紊乱的相关性. 中国优生与遗传杂志, 2023, 31(12): 2465-2471.
13. Yildizhan R, Kurdoglu M, Adali E, et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet, 2009, 280(4): 559-563.
14. Moin ASM, Sathyapalan T, Atkin SL, et al. Inflammatory markers in non-obese women with polycystic ovary syndrome are not elevated and show no correlation with vitamin D metabolites. Nutrients, 2022, 14(17): 3540.
15. Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
16. Ference BA, Holmes MV, Smith GD. Using Mendelian randomization to improve the design of randomized trials. Cold Spring Harb Perspect Med, 2021, 11(7): a040980.
17. Qi L. Mendelian randomization in nutritional epidemiology. Nutr Rev, 2009, 67(8): 439-450.
18. Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: a review. Res Synth Methods, 2019, 10(4): 486-496.
19. Sanderson E. Multivariable Mendelian randomization and mediation. Cold Spring Harb Perspect Med, 2021, 11(2): a038984.
20. Várbíró S, Takács I, Tűű L, et al. Effects of vitamin D on fertility, pregnancy and polycystic ovary syndrome-a review. Nutrients, 2022, 14(8): 1649.
21. Dastorani M, Aghadavod E, Mirhosseini N, et al. The effects of vitamin D supplementation on metabolic profiles and gene expression of insulin and lipid metabolism in infertile polycystic ovary syndrome candidates for in vitro fertilization. Reprod Biol Endocrinol, 2018, 16(1): 94.
22. 柳雨雨, 袁涛, 李海鸿, 等. 维生素D治疗多囊卵巢综合征有效性的Meta分析. 中国循证医学杂志, 2020, 20(6): 695-701.
23. 杨婷, 陈琳, 程薇, 等. 多囊卵巢综合征肥胖患者血清维生素D、铁蛋白水平、sICAM-1与胰岛素抵抗、糖脂代谢指标的相关性. 现代生物医学进展, 2022, 22(12): 2318-2321,2327.
24. 朱晓霞, 夏朋滨, 何亚琼. 补充维生素D联合益生菌对多囊卵巢综合征患者肠道菌群多样性、代谢和激素水平的影响. 中国微生态学杂志, 2020, 32(3): 317-321.
25. 贾新转, 魏兰, 甄秀丽. 维生素D联合二甲双胍及中药对PCOS患者内分泌代谢紊乱的治疗作用分析. 时珍国医国药, 2014, 25(6): 1415-1417.
26. Ostadmohammadi V, Jamilian M, Bahmani F, et al. Vitamin D and probiotic co-supplementation affects mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome. J Ovarian Res, 2019, 12(1): 5.
27. Ağar M, Güngör K, Güngör ND, et al. Vitamin D supplementation inhibits NF-kß signaling pathway in lean and obese women with PCOS. Eur Rev Med Pharmacol Sci, 2022, 26(11): 3973-3977.
28. 周加敏, 吴婷婷, 陈琳, 等. 维生素D缺乏与多囊卵巢综合征发病机制的相关性研究. 南京医科大学学报(自然科学版), 2023, 43(7): 934-944.
29. Gao B, Zhang C, Wang D, et al. Causal association between low vitamin D and polycystic ovary syndrome: a bidirectional mendelian randomization study. J Ovarian Res, 2024, 17(1): 95.
30. Contreras-Bolívar V, García-Fontana B, García-Fontana C, et al. Mechanisms involved in the relationship between vitamin D and insulin resistance: impact on clinical practice. Nutrients, 2021, 13(10): 3491.
31. Merhi Z. Crosstalk between advanced glycation end products and vitamin D: a compelling paradigm for the treatment of ovarian dysfunction in PCOS. Mol Cell Endocrinol, 2019, 479: 20-26.
32. Nowak A, Wojtowicz M, Baranski K, et al. The correlation of vitamin D level with body mass index in women with PCOS. Ginekol Pol, 2023, 94(11): 883-888.
33. Dokuzeylül Güngör N, Güngör K, Celik N, et al. Impact of body mass index and vitamin D on serum AMH levels and antral follicle count in PCOS. Eur Rev Med Pharmacol Sci, 2023, 27(1): 179-187.
34. Saglam Z, Bakir V L, Atas M N, et al. Role of VDR gene polymorphisms and vitamin D levels in normal and overweight patients with PCOS. J Genet, 2024, 103: 7.
35. Shi XY, Huang AP, Xie DW, et al. Association of vitamin D receptor gene variants with polycystic ovary syndrome: a meta-analysis. BMC Med Genet, 2019, 20(1): 32.
36. Nestler J E, Reilly E R, Cheang K I, et al. A pilot study: effects of decreasing serum insulin with diazoxide on vitamin D levels in obese women with polycystic ovary syndrome. Trans Am Clin Climatol Assoc, 2012, 123: 209-219.
37. Eftekhar M, Mirhashemi ES, Molaei B, et al. Is there any association between vitamin D levels and polycystic ovary syndrome (PCOS) phenotypes. Arch Endocrinol Metab, 2020, 64(1): 11-16.
38. Davis EM, Peck JD, Hansen KR, et al. Associations between vitamin D levels and polycystic ovary syndrome phenotypes. Minerva Endocrinol, 2019, 44(2): 176-184.

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