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.

中文翻译：

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循环维生素 D 浓度与乳腺癌和前列腺癌的风险：孟德尔随机研究。


背景 观察性研究表明，循环维生素 D 浓度 [25(OH)D] 与乳腺癌和前列腺癌风险之间存在关联，但最近的孟德尔随机化 (MR) 分析（包括 15 748 例乳腺癌和 22 898 例前列腺癌）并不支持这一点。案例。事实证明，证明因果关系具有挑战性，MR 研究的一个常见局限性是功效不足。方法 我们的目的是通过使用有史以来最大的全基因组关联研究的汇总数据来确定维生素 D 的循环浓度是否与乳腺癌和前列腺癌的风险存在因果关系（N = 73 699）、乳腺癌和前列腺癌。癌症（Ncase = 122 977）和前列腺癌（Ncase = 79 148）。我们使用六种常见的遗传变异（与之前的四种变异相比）构建了更强大的仪器，并应用了几种两样本 MR 方法。结果 我们发现没有证据支持 25(OH)D 与乳腺癌风险之间存在因果关系 [OR 每增加 25 nmol/L，1.02（95% 置信区间：0.97-1.08），P = 0.47]，雌激素受体（ ER)+ [1.00 (0.94-1.07), P = 0.99] 或 ER- [1.02 (0.90-1.16), P = 0.75] 亚型，前列腺癌 [1.00 (0.93-1.07), P = 0.99] 或晚期亚型[1.02 (0.90-1.16), P = 0.72] 使用逆方差加权方法。敏感性分析没有揭示任何定向多效性的迹象。结论 尽管样本量增加了近五倍并且统计功效显着提高，但我们的 MR 分析并不支持循环 25(OH)D 浓度对乳腺癌或前列腺癌风险的因果影响。然而，我们仍然不能排除维生素 D 的适度或非线性作用。 未来的研究可能旨在了解维生素 D 对严重缺乏的亚群的影响。