Is the Mendelian randomisation approach useful for vitamin D and cancer risk?
The recent paper by Dimitrakopoulou and colleagues reported that a Mendelian randomisation (MR) study of four single nucleotide polymorphisms (SNPs) related to serum 25-hydroxyvitamin D [25(OH)D] concentrations found no evidence that 25(OH)D concentrations were related to risk of seven types of cancer: breast, colorectal, lung, ovarian, neuroblastoma, pancreatic, or prostate cancer.1 Other MR studies to date also found very little support for vitamin D reducing risk of cancer. This state of affairs begs the question whether MR studies are an appropriate tool to use in evaluating the role of vitamin D in reducing risk of cancer.
There have been several approaches used to investigate the role of vitamin D in reducing risk of cancer: geographical ecological studies, occupational UVB exposure, and prospective studies based on measured serum 25(OH)D concentrations as well as related case-control studies, prospective studies based on predicted 25(OH)D concentrations, clinical trials, and studies of mechanisms.
Ecological studies have reported inverse correlations between solar UVB doses and incidence and/or mortality rates for over 20 types of cancer in six midlatitude countries.2 All of the cancers in Ref. 1 except neuroblastoma have been found to have risk inversely correlated with solar UVB, with the number of countries indicating the strength of the association: colorectal, six; breast, five; pancreatic, four; ovarian, three; lung and prostate, two. These studies generally include other cancer risk-modifying factors in the analysis. The primary physiological effect of UVB exposure is production of vitamin D, and other factors also related to solar UVB doses such as temperature cannot explain the findings.
A related study of cancer incidence with respect to occupation using lip cancer less lung cancer as the index of UVB exposure found inverse correlations for 14 types of cancer.3
Prospective studies based on measured 25(OH)D concentration strongly support the role of vitamin D in reducing risk of colorectal cancer as mentioned in the paper. For breast cancer, a meta-analysis of 11 case-control studies from seven countries found a very pronounced inverse correlation between 25(OH)D concentration and breast cancer incidence.4,5 It is often stated that case-control studies are unreliable because the disease state might affect 25(OH)D concentrations. However, the fact that the 25(OH)D concentration-breast cancer incidence relations for the 11 countries have very similar functional fits argues against that assumption.
Predicted 25(OH)D concentrations, which are based on determining 25(OH)D concentrations for a subsample of the group in relation to oral intake and solar UVB doses, have been used to show inverse correlations for breast,6 colorectal,7 and pancreatic cancer.7,8 Two other reviews support the role of vitamin D in reducing risk of pancreatic cancer.9,10
The mechanisms whereby vitamin D reduces risk of cancer incidence and death are well known and have been reported for breast,2,11-13 colorectal,13 and pancreatic cancer.10
Clinical trials are considered the gold standard for establishing causality. There have been three clinical trials that found reduced risk of cancer incidence with vitamin D plus calcium supplementation. The first found a significant reduction in cancer incidence for calcium plus vitamin D compared to a non-significant finding for calcium alone.14 The second was a reanalysis of the data from the Women's Health Initiative study. The abstract states: "In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26).".15 The third clinical trial found a marginally non-significant reduced risk (P=0.06) of total cancer for women taking 2000 IU/d vitamin D3 plus 1500 mg/d calcium.16 An analysis of the results based on modeled 25(OH)D concentrations of the participants using the 25(OH)D concentration-breast cancer incidence relationship found that the results were consistent with the number of participants and the 4-year duration of the study.5 The authors of that study also analyzed cancer risk with respect to the most recent serum 25(OH)D concentration prior to cancer diagnosis, finding significantly reduced risk for those with 25(OH)D concentration between 40 and 80 ng/ml (for nmol/L, divide by 2.5).
Noteworthy is that a previous study that did not find a significant relationship between genetic factors affecting serum 25(OH)D concentration and risk of colorectal cancer did find a very significant inverse correlation with respect to serum 25(OH)D concentration for the same participants.17 That study had 2,001 cases and 2,237 controls from a case-control study in Scotland. The authors noted that perhaps larger numbers are required for MR studies. However, a more important problem, mentioned in Ref. 1, is that the 25(OH)D concentration-cancer incidence relationship is very nonlinear. The odds ratio for breast cancer incidence changes with respect to 25(OH)D concentration; the ratios for 10-ng/ml intervals range are: 1.78 from 10 to 20 ng/ml; 1.40 from 20 to 30 ng/ml; 1.27 from 30 to 40 ng/ml; and 1.20 from 40 to 50 ng/ml.5 Unfortunately for MR studies, it is unlikely that many subjects with low 25(OH)D concentrations are included, and even if they were, there is no way to factor in actual 25(OH)D concentrations. A third problem with MR studies is, as the authors state, that the SNPs used represent only 5% of those known to affect 25(OH)D concentrations.18 Studying SNPs that have tiny effect on 25(OH)D is now may be a step toward understanding the physiology of vitamin D, but there is not enough information yet available to do a meaningful MR analysis of the type incorrectly used for this purpose. The information that we have to date indicates that serum 25(OH)D and risk of cancer are almost wholly determined by environment and diet, and not known SNPs.
Thus, ecological, occupational UVB exposure, observational and mechanistic studies, and clinical trials, together provide strong support for the role of vitamin D in reducing risk of many types of cancer, whereas the MR approach does not. Given that fact, the logical conclusion is that MR studies at present are unable to accurately determine for which cancers vitamin D reduces risk.
William B. Grant,1 and Cedric F. Garland2
2 Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, 9500 Gilman Drive 0620, La Jolla, CA 92093-0620, USA.
1. Dimitrakopoulou VI, Tsilidis KT, Haycock PC, et al. Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study. BMJ 2017;359:j4761
2. Wang S, Huo D, Kupfer S, et al. Genetic variation in the Vitamin D related pathway and breast cancer risk in women of African ancestry in the Root Consortium. 2017 Sep 10. doi: 10.1002/ijc.31038. [Epub ahead of print]
3. Ordóñez-Mena JM, Schöttker B, Saum KU, et al. No association of vitamin D pathway genetic variants with cancer risks in a population-based cohort of German older adults. Cancer Epidemiol Biomarkers Prev. 2017;26:1459–61.
4 Theodoratou E, Palmer T, Zgaga L, et al. Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: a mendelian randomization analysis. PLoS One. 2012;7:e37662.
5. Trummer O, Langsenlehner U, Krenn-Pilko S, et al. Vitamin D and prostate cancer prognosis: a Mendelian randomization study. World J Urol. 2016;34:607–11.
6. Ong JS, Cuellar-Partida G, Lu Y, et al. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. Int J Epidemiol. 2016 45:1619–30
7. Wu X, Cheng J, Yang K. Vitamin D-related gene polymorphisms, plasma 25-hydroxy-vitamin D, cigarette smoke and non-small cell lung cancer (NSCLC) risk. Int J Mol Sci. 2016;17. pii: E1597.
8. Afzal S, Brøndum-Jacobsen P, Bojesen SE, Nordestgaard BG. Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts. BMJ. 2014;349:g6330.
9. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993–4023
10. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol. 2012;4:203–11.
11. Grant WB. 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case–control versus nested case–control studies, Anticancer Res. 2015;35:1153–60.
12. Grant WB, Boucher BJ. Randomized controlled trials of vitamin D and cancer incidence: A modeling study. PLos One. 2017;12:e0176448.
13. Palmer JR, Gerlovin H, Bethea TN, et al. Predicted 25-hydroxyvitamin D in relation to incidence of breast cancer in a large cohort of African American women. Breast Cancer Res. 2016;18:86.
14. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. JNCI 2006; 98:451–9.
15. Bao Y, Ng K, Wolpin BM, et al. Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies. Br J Cancer. 2010;102:1422–7.
16. Wolpin BM, Ng K, Bao Y, et al. Plasma 25-hydroxyvitamin D and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2012;21:82–91.
17. Altieri B, Grant WB, Della Casa S, et al. Vitamin D and pancreas: the role of sunshine vitamin in the pathogenesis of diabetes mellitus and pancreatic cancer. Crit Rev Food Sci Nutr. 2017;57:3472–88.
18. Feldman D, Krishnan AV, Swami S, et al. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014;14:342–57.
19. Aggarwal A, Feldman D, Feldman BJ. Identification of tumor-autonomous and indirect effects of vitamin D action that inhibit breast cancer growth and tumor progression. J Steroid Biochem Mol Biol. 2017 Jul 11. pii: S0960-0760(17)30167-X. doi: 10.1016/j.jsbmb.2017.07.003. [Epub ahead of print] Review.
20. Moukayed M, Grant WB. The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: a review of the epidemiology, clinical trials, and mechanisms. Rev Endocr Metab Disord. 2017;18:167–82.
21. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011;94:1144–9.
21. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586–91.
23. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. JAMA. 2017;317:1234–43.
24. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011:31: 617–22.
25. Grant WB, Boucher BJ, Bhattoa HJ, Lahore. Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. JSBMB. J Steroid Biochem Mol Biol. 2017 Aug 22. pii: S0960-0760(17)30223-6. doi: 10.1016/j.jsbmb.2017.08.009. [Epub ahead of print]
26. Hiraki LT, Major JM, Chen C, et al. Exploring the genetic architecture of circulating 25-hydroxyvitamin D. Genet Epidemiol. 2013;37:92–8.
Competing interests: I receive funding from Bio-Tech Pharmacal (Fayetteville, AR, USA)