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dc.contributor.authorHe, Y
dc.contributor.authorTimofeeva, M
dc.contributor.authorFarrington, SM
dc.contributor.authorVaughan-Shaw, P
dc.contributor.authorSvinti, V
dc.contributor.authorWalker, M
dc.contributor.authorZgaga, L
dc.contributor.authorMeng, X
dc.contributor.authorLi, X
dc.contributor.authorSpiliopoulou, A
dc.contributor.authorJiang, X
dc.contributor.authorHyppönen, E
dc.contributor.authorKraft, P
dc.contributor.authorKiel, DP
dc.contributor.authorSUNLIGHT consortium
dc.contributor.authorHayward, C
dc.contributor.authorCampbell, A
dc.contributor.authorPorteous, D
dc.contributor.authorVucic, K
dc.contributor.authorKirac, I
dc.contributor.authorFilipovic, M
dc.contributor.authorHarris, SE
dc.contributor.authorDeary, IJ
dc.contributor.authorHoulston, R
dc.contributor.authorTomlinson, IP
dc.contributor.authorCampbell, H
dc.contributor.authorTheodoratou, E
dc.contributor.authorDunlop, MG
dc.date.accessioned2019-02-25T16:05:23Z
dc.date.issued2018-08-14
dc.identifier.citationBMC medicine, 2018, 16 (1), pp. 142 - ?
dc.identifier.issn1741-7015
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3083
dc.identifier.eissn1741-7015
dc.identifier.doi10.1186/s12916-018-1119-2
dc.description.abstractBACKGROUND: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.formatElectronic
dc.format.extent142 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectSUNLIGHT consortium
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectVitamin D
dc.subjectRisk Factors
dc.subjectCase-Control Studies
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectMendelian Randomization Analysis
dc.titleExploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.
dc.typeJournal Article
dcterms.dateAccepted2018-07-06
rioxxterms.versionofrecord10.1186/s12916-018-1119-2
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-08-14
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBMC medicine
pubs.issue1
pubs.notesNot 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-statusPublished
pubs.volume16
pubs.embargo.termsNot known
icr.researchteamCancer Genomicsen_US
dc.contributor.icrauthorHoulston, Richarden


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