The association between Vitamin D and breast cancer: A two-sample Mendelian randomization study

Abstract

Introduction: Breast cancer, as a significant threat to women’s health globally, has a complex pathogenesis. Vitamin D, a steroid hormone with diverse physiological functions, has garnered increasing attention in breast cancer research. Numerous studies have been conducted to elucidate the relationship between Vitamin D and breast cancer, yet no definitive conclusions have been reached.

Objective: Hence, in this study, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the association between Vitamin D and breast cancer.

Methods: Genetic variants associated with Vitamin D levels and breast cancer data were obtained from the genome-wide association study database and version R11 of the FinnGen study dataset, respectively. The inverse variance-weighted (IVW) method served as the primary analytical approach, supplemented by various sensitivity analyses. Horizontal pleiotropy was tested using MR-Egger and MR-Pleiotropy RESidual Sum and Outlier methods, while sensitivity analysis was conducted using the leave-one-out method to assess the reliability of the results.

Results: Based on instrumental variable assumptions, 111 single nucleotide polymorphisms were suitable for subsequent analyses after matching the results. The MR analysis demonstrated no evidence of a causal relationship between Vitamin D and breast cancer. The IVW method yielded a non-significant association (p=0.968; odds ratio = 1.002, 95% confidence interval: 0.896 - 1.119), and the other methods pointed out the same direction of effect, and the subsequent pleiotropic analysis and sensitivity analysis confirmed the accuracy of the results.

Conclusion: At the genetic level, no causal relationship between Vitamin D and breast cancer was found; thus, our findings do not support a clinically significant role of Vitamin D supplementation in breast cancer risk reduction.

Keywords

Vitamin D / Breast cancer / Mendelian randomization

Funding

None.

Conflict of interest

The authors declare no competing interests.

References

[1] Forouzanfar MH, Foreman KJ, Delossantos AM, et al. Breast and cervical cancer in 187 countries between 1980 and 2010: A systematic analysis. Lancet. 2011; 378(9801):1461-1484. doi: 10.1016/s0140-6736(11)61351-2

[2] Greco KE, Mahon SM. The state of genomic health care and cancer. Are we going two steps forward and one step backward? Annu Rev Nurs Res. 2011; 29:73-97.doi: 10.1891/0739-6686.29.73

[3] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Can J Clin. 2021; 71(3):209-249. doi: 10.3322/caac.21660

[4] Hortobagyi GN, De la Garza Salazar J, Pritchard K, et al. The global breast cancer burden: Variations in epidemiology and survival. Clin Breast Cancer. 2005; 6(5):391-401. doi: 10.3816/cbc.2005.n.043

[5] Wheeler SB, Reeder-Hayes KE, Carey LA. Disparities in breast cancer treatment and outcomes: Biological, social, and health system determinants and opportunities for research. Oncologist. 2013; 18(9):986-993. doi: 10.1634/theoncologist.2013-0243

[6] Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017; 18(2):153-165. doi: 10.1007/s11154-017-9424-1

[7] Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014; 14(5):342-357. doi: 10.1038/nrc3691

[8] Bhamb N, Kanim L, Maldonado R, Svet M, Metzger M. Effect of modulating dietary vitamin D on the general bone health of rats during posterolateral spinal fusion. J Orthop Res. 2018; 36(5):1435-1443. doi: 10.1002/jor.23832

[9] Anderson PH, Atkins GJ, Turner AG, Kogawa M, Findlay DM, Morris HA. Vitamin D metabolism within bone cells: Effects on bone structure and strength. Mol Cell Endocrinol. 2011; 347(1-2):42-47. doi: 10.1016/j.mce.2011.05.024

[10] Shin MH, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC. Intake of dairy products, calcium, and vitamin d and risk of breast cancer. J Natl Cancer Inst. 2002; 94(17): 1301-1311. doi: 10.1093/jnci/94.17.1301

[11] Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat. 2010; 121(2):469-477. doi: 10.1007/s10549-009-0593-9

[12] Bidgoli SA, Azarshab H. Role of vitamin D deficiency and lack of sun exposure in the incidence of premenopausal breast cancer: A case control study in Sabzevar, Iran. Asian Pac J Cancer Prev APJCP. 2014; 15(8):3391-3396. doi: 10.7314/apjcp.2014.15.8.3391

[13] O’Brien KM, Sandler DP, Taylor JA, Weinberg CR. Serum vitamin D and risk of breast cancer within five years. Environ Health Perspect. 2017; 125(7):077004. doi: 10.1289/ehp943

[14] Hossain S, Beydoun MA, Beydoun HA, Chen X, Zonderman AB, Wood RJ. Vitamin D and breast cancer: A systematic review and meta-analysis of observational studies. Clin Nutr ESPEN. 2019; 30:170-184. doi: 10.1016/j.clnesp.2018.12.085

[15] Knight JA, Lesosky M, Barnett H, Raboud JM, Vieth R. Vitamin D and reduced risk of breast cancer: A population-based case-control study. Cancer Epidemiol Biomarkers Prev. 2007; 16(3):422-429. doi: 10.1158/1055-9965.Epi-06-0865

[16] McCullough ML, Rodriguez C, Diver WR, et al. Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the cancer prevention study II nutrition cohort. Cancer Epidemiol Biomarkers Prev. 2005; 14(12):2898-2904. doi: 10.1158/1055-9965.Epi-05-0611

[17] Rossi M, McLaughlin JK, Lagiou P, et al. Vitamin D intake and breast cancer risk: A case-control study in Italy. Ann Oncol. 2009; 20(2):374-378. doi: 10.1093/annonc/mdn550

[18] O’Brien KM, Keil AP, Harmon QE, et al. Vitamin D supplement use and risk of breast cancer by race-ethnicity. Epidemiology. 2022; 33(1):37-47. doi: 10.1097/ede.0000000000001413

[19] Qin B, Xu B, Ji N, et al. Intake of vitamin D and calcium, sun exposure, and risk of breast cancer subtypes among black women. Am J Clin Nutr. 2020; 111(2):396-405. doi: 10.1093/ajcn/nqz302

[20] Anderson LN, Cotterchio M, Vieth R, Knight JA. Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. Am J Clin Nutr. 2010; 91(6):1699-1707. doi: 10.3945/ajcn.2009.28869

[21] Abbas S, Linseisen J, Rohrmann S, et al. Dietary intake of vitamin D and calcium and breast cancer risk in the European prospective investigation into cancer and nutrition. Nutr Cancer. 2013; 65(2):178-187. doi: 10.1080/01635581.2013.752018

[22] Kuper H, Yang L, Sandin S, Lof M, Adami HO, Weiderpass E. Prospective study of solar exposure, dietary vitamin D intake, and risk of breast cancer among middle-aged women. Cancer Epidemiol Biomarkers Prev. 2009; 18(9):2558-2561. doi: 10.1158/1055-9965.Epi-09-0449

[23] Oghabi Bakhshaiesh T, Nazeri E, Jafarbeik-Iravani N, Shirvani-Farsani Z, Esmaeili R. Vitamin D and breast cancer risk: A systematic review and meta-analysis in Iranian patients. Ann Med Surg (Lond). 2022; 80:104162. doi: 10.1016/j.amsu.2022.104162

[24] Song D, Deng Y, Liu K, et al. Vitamin D intake, blood vitamin D levels, and the risk of breast cancer: A dose-response meta-analysis of observational studies. Aging. 2019; 11(24):12708-12732. doi: 10.18632/aging.102597

[25] Li Z, Wu L, Zhang J, Huang X, Thabane L, Li G. Effect of vitamin D supplementation on risk of breast cancer: A systematic review and meta-analysis of randomized controlled trials. Front Nutr. 2021; 8:655727. doi: 10.3389/fnut.2021.655727

[26] Davey Smith G, Hemani G. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014; 23(R1):R89-R98. doi: 10.1093/hmg/ddu328

[27] Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018; 50(5):693-698. doi: 10.1038/s41588-018-0099-7