Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study
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
BMC medicine · 58 citations
How it was studied
- Design
- Randomized controlled trial (indexed by PubMed)
- Studied in
- People
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Nonprofit
- Wellcome Trust
- Nonprofit
- Cancer Research UK
- Nonprofit
- Age UK
- Government
- China Scholarship Council
- University or hospital
- Centre for Cognitive Ageing and Cognitive Epidemiology
- Government
- Directorate for Biological Sciences
- Government
- Medical Research Council
- Government
- Biotechnology and Biological Sciences Research Council
- Government
- National Cancer Institute
- Government
- Chief Scientist Office
- Government
- NCI NIH HHS
- Grants
- Medical Research Council (MR/M004007/1); Medical Research Council (MR/K026992/1); Cancer Research UK (C348/ A18927); Cancer Research UK (C31250/A22804); Cancer Research UK (16459); National Cancer Institute (R35CA197449); Cancer Research UK (18927); Medical Research Council (MC_UU_00007/1); Biotechnology and Biological Sciences Research Council (BB/F019394/1); Medical Research Council (MR/K026992/1); National Cancer Institute (U01 CA167551); Medical Research Council (MC_PC_17228); Biotechnology and Biological Sciences Research Council (BB/F019394/1); Cancer Research UK (12076); Medical Research Council (MC_UU_00007/10); Medical Research Council (MR/K018647/1); Cancer Research UK (22804)
Based on 11 listed funder(s).
Publication
- Published
- 2018-08-13 · BMC Med · vol. 16 · issue 1 · p. 142
- Publisher
- BioMed Central
- Cited
- 82 citations · more than 99% of similar papers · 8.4× the field average
- Impact
- Top 10% most cited in its field
- References
- 67 works
- Access
- Open access (journal) · CC-BY
- Research areas
- Vitamin D Research Studies · Gut microbiota and health · Nutritional Studies and Diet
- Keywords
- Medicine, Causality (physics), Colorectal cancer, Mendelian randomization, Internal medicine, Oncology, Vitamin D and neurology, Cancer, Genetics, Genotype, Gene
- MeSH
- humans, colorectal neoplasms, vitamin d, risk factors, case-control studies, middle aged, female, male, mendelian randomization analysis
27 authors
From CN, GB, IE, US, SE, AU, HR, CA
- Yazhou HeSichuan University; Western General Hospital; Institute of Genetics and Cancer; Medical Research Council; University of Edinburgh
- Maria N TimofeevaWestern General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Susan Mary FarringtonWestern General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Peter G Vaughan-ShawWestern General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Victoria SvintiWestern General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Marion WalkerWestern General Hospital; Institute of Genetics and Cancer; Medical Research Council
Abstract
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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