| Title: | Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study |
| Journal: | BMC Medicine |
| Published: | 14 Aug 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30103784/ |
| DOI: | https://doi.org/10.1186/s12916-018-1119-2 |
| URL: | https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-018-1119-2 |
Publication 8559
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Abstract
BackgroundWhilst 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.MethodsWe 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.ResultsThe 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).ConclusionsDespite 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.</p>
28 Authors
- Yazhou He
- Maria Timofeeva
- Susan M. Farrington
- Peter Vaughan-Shaw
- Victoria Svinti
- Marion Walker
- Lina Zgaga
- Xiangrui Meng
- Xue Li
- Athina Spiliopoulou
- Xia Jiang
- Elina Hyppönen
- Peter Kraft
- Douglas P. Kiel
- The SUNLIGHT consortium
- Caroline Hayward
- Archie Campbell
- David Porteous
- Katarina Vucic
- Iva Kirac
- Masa Filipovic
- Sarah E. Harris
- Ian J. Deary
- Richard Houlston
- Ian P. Tomlinson
- Harry Campbell
- Evropi Theodoratou
- Malcolm G. Dunlop
1 Application
| Application ID | Title |
|---|---|
| 7441 | Investigation of genetic, environment and gene ? environment interaction in colorectal cancer risk and survival |
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