Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study.
BACKGROUND
Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power.


METHODS
We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods.


RESULTS
We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy.


CONCLUSIONS
Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.
['Jiang|Xia|X|', 'Dimou|Niki L|NL|', 'Al-Dabhani|Kawthar|K|', 'Lewis|Sarah J|SJ|', 'Martin|Richard M|RM|', 'Haycock|Philip C|PC|', 'Gunter|Marc J|MJ|', 'Key|Timothy J|TJ|', 'Eeles|Rosalind A|RA|', 'Muir|Kenneth|K|', 'Neal|David|D|', 'Giles|Graham G|GG|', 'Giovannucci|Edward L|EL|', 'Stampfer|Meir|M|', 'Pierce|Brandon L|BL|', 'Schildkraut|Joellen M|JM|', 'Warren Andersen|Shaneda|S|', 'Thompson|Deborah|D|', 'Zheng|Wei|W|', 'Kraft|Peter|P|', 'Tsilidis|Konstantinos K|KK|', '|||']
D000368:Aged D001943:Breast Neoplasms D015984:Causality D005260:Female D055106:Genome-Wide Association Study D006801:Humans D008297:Male D057182:Mendelian Randomization Analysis D008875:Middle Aged D020641:Polymorphism, Single Nucleotide D011471:Prostatic Neoplasms D011960:Receptors, Estrogen D012307:Risk Factors D014807:Vitamin D
breast prostate Mendelian randomization malignancy serum vitamin D concentrations