Bidirectional Mendelian randomisation analysis of the relationship between circulating vitamin D concentration and colorectal cancer risk
Bidirectional Mendelian randomisation analysis of the relationship between circulating vitamin D concentration and colorectal cancer risk
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DOI：
10.1002/ijc.33779
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发表时间：
2021-09-06
影响因子：
6.4
通讯作者：
Dunlop, Malcolm G.
中科院分区：
文献类型：
--
作者：
He, Yazhou;Zhang, Xiaomeng;Dunlop, Malcolm G.
流行病学证据与维生素D对结直肠癌（CRC）的保护作用一致，但观察到的强相关性对混杂因素和潜在的反向因果关系是开放的。以前的孟德尔随机化（MR）研究受到遗传工具差和统计能力不足的限制。此外，遗传性高CRC风险是否会影响维生素D水平，即反向因果关系，仍然未知。在此，我们报告了第一个双向MR研究。我们采用了110种新发现的遗传变异作为维生素D的替代物，以获得对26397例CRC病例和41481例欧洲血统对照的CRC风险的无混杂效应估计。为了测试储备因果关系，我们估计了来自英国生物库的417580名参与者中115种CRC风险变异对维生素D水平的影响。因果关系采用随机效应逆方差加权（IVW）法进行估计。我们发现维生素D对CRC风险没有显著的因果关系[IVW估计比值比：0.97，95%置信区间（CI）= 0.88-1.07，P = 0.565]。同样，遗传性CRC风险增加与维生素D水平之间没有显著的反向因果关系（IVW估计β：-0.002，95%CI = -0.008至0.004，P = .543）。按肿瘤部位进行的分层分析没有发现维生素D与结肠癌或直肠癌之间存在显著的因果关系。尽管这项研究的统计学功效有所提高，但我们没有发现循环维生素D和CRC风险之间存在因果关系的证据。观察性研究报告的显著相关性可能主要由未识别的混杂因素驱动。
Epidemiological evidence is consistent with a protective effect of vitamin D against colorectal cancer (CRC), but the observed strong associations are open to confounders and potential reverse causation. Previous Mendelian randomisation (MR) studies were limited by poor genetic instruments and inadequate statistical power. Moreover, whether genetically higher CRC risk can influence vitamin D level, namely the reverse causation, still remains unknown. Herein, we report the first bidirectional MR study. We employed 110 newly identified genetic variants as proxies for vitamin D to obtain unconfounded effect estimates on CRC risk in 26 397 CRC cases and 41 481 controls of European ancestry. To test for reserve causation, we estimated effects of 115 CRC-risk variants on vitamin D level among 417 580 participants from the UK Biobank. The causal association was estimated using the random-effect inverse-variance weighted (IVW) method. We found no significant causal effect of vitamin D on CRC risk [IVW estimate odds ratio: 0.97, 95% confidence interval (CI) = 0.88-1.07, P = .565]. Similarly, no significant reverse causal association was identified between genetically increased CRC risk and vitamin D levels (IVW estimate beta: -0.002, 95% CI = -0.008 to 0.004, P = .543). Stratified analysis by tumour sites did not identify significant causal associations in either direction between vitamin D and colon or rectal cancer. Despite the improved statistical power of this study, we found no evidence of causal association of either direction between circulating vitamin D and CRC risk. Significant associations reported by observational studies may be primarily driven by unidentified confounders.