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 citas
Cómo se estudió
- Diseño
- Ensayo controlado aleatorizado (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Eventos clínicos como enfermedad o muerte
Quién lo pagó
- Financiación
- Financiación independiente
- Organización sin fines de lucro
- Wellcome Trust
- Organización sin fines de lucro
- Cancer Research UK
- Organización sin fines de lucro
- Age UK
- Gobierno
- China Scholarship Council
- Universidad u hospital
- Centre for Cognitive Ageing and Cognitive Epidemiology
- Gobierno
- Directorate for Biological Sciences
- Gobierno
- Medical Research Council
- Gobierno
- Biotechnology and Biological Sciences Research Council
- Gobierno
- National Cancer Institute
- Gobierno
- Chief Scientist Office
- Gobierno
- NCI NIH HHS
- Subvenciones
- 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)
Según 11 financiadores declarados.
Publicación
- Publicado
- 2018-08-13 · BMC Med · vol. 16 · número 1 · pág. 142
- Editorial
- BioMed Central
- Citado
- 82 citas · más que el 99% de estudios similares · 8.4× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 67 trabajos
- Acceso
- Acceso abierto (revista) · CC-BY
- Áreas de investigación
- Vitamin D Research Studies · Gut microbiota and health · Nutritional Studies and Diet
- Palabras clave
- 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 autores
- Yazhou He🇨🇳🇬🇧Sichuan University; Western General Hospital; Institute of Genetics and Cancer; Medical Research Council; University of Edinburgh
- Maria N Timofeeva🇬🇧Western General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Susan Mary Farrington🇬🇧Western General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Peter G Vaughan-Shaw🇬🇧Western General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Victoria Svinti🇬🇧Western General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Marion Walker🇬🇧Western General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Lina Zgaga🇮🇪🇬🇧Trinity College Dublin; Western General Hospital; Institute of Genetics and Cancer; Medical Research Council
- Xiangrui Meng🇬🇧University of Edinburgh
- Xue Li🇬🇧University of Edinburgh
- Athina Spiliopoulou🇬🇧University of Edinburgh
- Xia Jiang🇺🇸🇸🇪Harvard University; Karolinska Institutet
- Elina Hyppönen🇦🇺🇬🇧University of South Australia; Great Ormond Street Hospital; University College London
- Peter Kraft🇺🇸Harvard University
- Douglas P. Kiel🇺🇸Broad Institute; Beth Israel Deaconess Medical Center; Harvard University; Hebrew SeniorLife; Massachusetts Institute of Technology
- Caroline Hayward🇬🇧Western General Hospital; Institute of Genetics and Cancer; University of Edinburgh
- Archie M Campbell🇬🇧Western General Hospital; University of Edinburgh
- David John Porteous🇬🇧Western General Hospital; University of Edinburgh
- Katarina Vučić🇭🇷Agency for Medicinal Products and Medical Devices of Croatia
- Iva Kirac🇭🇷University Hospital Centre Zagreb
- Maša Filipović🇭🇷University of Zagreb
- Sarah E. Harris🇬🇧Edinburgh Cancer Research; University of Edinburgh
- Ian J. Deary🇬🇧University of Edinburgh
- Richard S. Houlston🇬🇧Institute of Cancer Research
- Ian P.M. Tomlinson🇬🇧University of Birmingham
- Harry Campbell🇬🇧Western General Hospital; Institute of Genetics and Cancer; Medical Research Council; University of Edinburgh
- Evropi Τheodoratou🇬🇧🇨🇦 · autor de correspondenciaWestern General Hospital; Edinburgh Cancer Research; Centre for Global Health Research; Institute of Genetics and Cancer; University of Edinburgh
- Malcolm G. Dunlop🇬🇧 · autor de correspondenciaWestern General Hospital; Institute of Genetics and Cancer; Medical Research Council
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
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