dc.contributor.author | He, Y | |
dc.contributor.author | Timofeeva, M | |
dc.contributor.author | Farrington, SM | |
dc.contributor.author | Vaughan-Shaw, P | |
dc.contributor.author | Svinti, V | |
dc.contributor.author | Walker, M | |
dc.contributor.author | Zgaga, L | |
dc.contributor.author | Meng, X | |
dc.contributor.author | Li, X | |
dc.contributor.author | Spiliopoulou, A | |
dc.contributor.author | Jiang, X | |
dc.contributor.author | Hyppönen, E | |
dc.contributor.author | Kraft, P | |
dc.contributor.author | Kiel, DP | |
dc.contributor.author | SUNLIGHT consortium, | |
dc.contributor.author | Hayward, C | |
dc.contributor.author | Campbell, A | |
dc.contributor.author | Porteous, D | |
dc.contributor.author | Vucic, K | |
dc.contributor.author | Kirac, I | |
dc.contributor.author | Filipovic, M | |
dc.contributor.author | Harris, SE | |
dc.contributor.author | Deary, IJ | |
dc.contributor.author | Houlston, R | |
dc.contributor.author | Tomlinson, IP | |
dc.contributor.author | Campbell, H | |
dc.contributor.author | Theodoratou, E | |
dc.contributor.author | Dunlop, MG | |
dc.date.accessioned | 2019-02-25T16:05:23Z | |
dc.date.issued | 2018-08-14 | |
dc.identifier.citation | BMC medicine, 2018, 16 (1), pp. 142 - ? | |
dc.identifier.issn | 1741-7015 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3083 | |
dc.identifier.eissn | 1741-7015 | |
dc.identifier.doi | 10.1186/s12916-018-1119-2 | |
dc.description.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. | |
dc.format | Electronic | |
dc.format.extent | 142 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | BMC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | SUNLIGHT consortium | |
dc.subject | Humans | |
dc.subject | Colorectal Neoplasms | |
dc.subject | Vitamin D | |
dc.subject | Risk Factors | |
dc.subject | Case-Control Studies | |
dc.subject | Middle Aged | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Mendelian Randomization Analysis | |
dc.title | Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-07-06 | |
rioxxterms.versionofrecord | 10.1186/s12916-018-1119-2 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-08-14 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | BMC medicine | |
pubs.issue | 1 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.publication-status | Published | |
pubs.volume | 16 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Genomics | |
dc.contributor.icrauthor | Houlston, Richard | |