Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.
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Date
2018-08-14ICR Author
Author
He, Y
Timofeeva, M
Farrington, SM
Vaughan-Shaw, P
Svinti, V
Walker, M
Zgaga, L
Meng, X
Li, X
Spiliopoulou, A
Jiang, X
Hyppönen, E
Kraft, P
Kiel, DP
SUNLIGHT consortium,
Hayward, C
Campbell, A
Porteous, D
Vucic, K
Kirac, I
Filipovic, M
Harris, SE
Deary, IJ
Houlston, R
Tomlinson, IP
Campbell, H
Theodoratou, E
Dunlop, MG
Type
Journal Article
Metadata
Show full item recordAbstract
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 × 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.
Collections
Subject
SUNLIGHT consortium
Humans
Colorectal Neoplasms
Vitamin D
Risk Factors
Case-Control Studies
Middle Aged
Female
Male
Mendelian Randomization Analysis
Research team
Cancer Genomics
Language
eng
Date accepted
2018-07-06
License start date
2018-08-14
Citation
BMC medicine, 2018, 16 (1), pp. 142 - ?
Publisher
BMC