期刊
BMC MEDICINE
卷 16, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12916-018-1119-2
关键词
Vitamin D; Colorectal cancer; Mendelian randomisation
资金
- Cancer Research UK [C348/A18927]
- MRC Human Genetics Unit Centre Grant [U127527202, U127527198]
- China Scholarship Council
- CRUK Career Development Fellowship [C31250/A22804]
- University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology
- Medical Research Council
- Biotechnology and Biological Sciences Research Council [MR/K026992/1, BB/F019394/1]
- Age UK (Disconnected Mind project)
- Medical Research Council UK
- Wellcome Trust (Wellcome Trust Strategic Award 'STratifying Resilience and Depression Longitudinally' (STRADL)) [104036/Z/14/Z]
- Scottish Executive Health Department, Chief Scientist Office [CZD/16/6]
- MRC
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [G0600237, MC_U127527198, MC_PC_U127527198, MC_PC_U127561128, MR/K018647/1, MC_UU_00007/10, G0600329, MC_UU_00007/1, MR/M004007/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- Medical Research Council [MR/K026992/1] Funding Source: researchfish
Background: Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. Methods: We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. Results: The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 x 10(-11)), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51-2.07, P= 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69-1.19, P= 0.48). Conclusions: Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.
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