机构：[1]Colon Cancer Genetics Group, Medical Research Council Human GeneticsUnit, Medical Research Council Institute of Genetics & Molecular Medicine,Western General Hospital, The University of Edinburgh, Edinburgh EH4 2XU,UK[2]West China School of Medicine/West China Hospital, Sichuan University,Chengdu 610041, People’s Republic of China四川大学华西医院[3]Centre for Global HealthResearch, Usher Institute of Population Health Sciences and Informatics, TheUniversity of Edinburgh, Edinburgh EH8 9AG, UK[4]Department of PublicHealth and Primary Care, Institute of Population Health, Trinity CollegeDublin, University of Dublin, Dublin 24, D02 PN40, Ireland[5]Program inGenetic Epidemiology and Statistical Genetics. Department of Epidemiology,Harvard T.H.Chan School of Public Health, 677 Huntington Avenue, Boston,MA 02115, USA[6]Unit of Cardiovascular Epidemiology, Institute ofEnvironmental Medicine, Karolinska Institutet, Nobels vagen 13, Stockholm17177, Sweden[7]Australian Centre for Precision Health, University of SouthAustralia Cancer Research Institute, University of South Australia, Adelaide, SA5001, Australia[8]Population, Policy and Practice, University College London,Great Ormond Street, Institute of Child Health, WC1E 6BT, London, UK[9]Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston,MA 02131, USA[10]Department of Medicine, Beth Israel Deaconess MedicalCenter and Harvard Medical School, Boston, MA 02115, USA[11]Broad Instituteof Harvard and Massachusetts Institute of Technology, Boston, MA 02142,USA[12]MRC Human Genetics Unit, MRC Institute of Genetics & MolecularMedicine, The University of Edinburgh, Western General Hospital, EdinburghEH4 2XU, UK[13]Generation Scotland, Institute of Genetics and MolecularMedicine, The University of Edinburgh, Western General Hospital Edinburgh,Crewe Road, Edinburgh EH4 2XU, UK[14]Agency for Medicinal Products andMedical Devices, Department for Quality, Safety and Efficacy Assessment,Zagreb, Croatia[15]Department of Surgical Oncology, University Hospital forTumours, Sestre milosrdnice University Hospital Centre, Zagreb, Croatia[16]School of Medicine, University of Zagreb, Zagreb, Croatia[17]Centre forCognitive Ageing and Cognitive Epidemiology, The University of Edinburgh,Edinburgh, UK[18]Centre for Genomic and Experimental Medicine, Institute ofGenetics and Molecular Medicine, The University of Edinburgh, Edinburgh,UK[19]Department of Psychology, The University of Edinburgh, Edinburgh, UK[20]Division of Genetics and Epidemiology, The Institute of Cancer Research,Sutton, Surrey SM2 5NG, UK[21]Institute of Cancer and Genomic Sciences,University of Birmingham, Birmingham, UK.
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.
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.
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).
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.
基金：
The work was also supported by a project grant (to MGD)
within the MRC Human Genetics Unit Centre Grant (U127527202 and
U127527198 from 1/4/18). YH, XL and XM are supported by the China
Scholarship Council. ET is supported by a CRUK Career Development
Fellowship (grant no.C31250/A22804). IJD and SEH are supported by the
University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology,
which is funded by the Medical Research Council and the Biotechnology and
Biological Sciences Research Council (grant no. MR/K026992/1). The Lothian Birth
Cohort studies are funded by Age UK (Disconnected Mind project) and the
Biotechnology and Biological Sciences Research Council (grant no. BB/F019394/1).
Genotyping of the GS:SFHS samples was carried out by the Edinburgh
Clinical Research Facility, University of Edinburgh, and was funded by the
Medical Research Council UK and the Wellcome Trust (Wellcome Trust
Strategic Award ‘STratifying Resilience and Depression Longitudinally’
(STRADL), Reference 104036/Z/14/Z). GS:SFHS received core support from
the Scottish Executive Health Department, Chief Scientist Office, grant
number CZD/16/6. The MRC provides core funding to the QTL in Health
and Disease research program at the MRC HGU, IGMM, University of
Edinburgh.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|1 区医学
小类|2 区医学：内科
最新[2023]版：
大类|1 区医学
小类|1 区医学：内科
第一作者：
第一作者机构：[1]Colon Cancer Genetics Group, Medical Research Council Human GeneticsUnit, Medical Research Council Institute of Genetics & Molecular Medicine,Western General Hospital, The University of Edinburgh, Edinburgh EH4 2XU,UK[2]West China School of Medicine/West China Hospital, Sichuan University,Chengdu 610041, People’s Republic of China[3]Centre for Global HealthResearch, Usher Institute of Population Health Sciences and Informatics, TheUniversity of Edinburgh, Edinburgh EH8 9AG, UK
共同第一作者：
通讯作者：
通讯机构：[1]Colon Cancer Genetics Group, Medical Research Council Human GeneticsUnit, Medical Research Council Institute of Genetics & Molecular Medicine,Western General Hospital, The University of Edinburgh, Edinburgh EH4 2XU,UK[3]Centre for Global HealthResearch, Usher Institute of Population Health Sciences and Informatics, TheUniversity of Edinburgh, Edinburgh EH8 9AG, UK
推荐引用方式(GB/T 7714)：
Yazhou He,Maria Timofeeva,Susan M. Farrington,et al.Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.[J].BMC medicine.2018,16(1):142.doi:10.1186/s12916-018-1119-2.
APA：
Yazhou He,Maria Timofeeva,Susan M. Farrington,Peter Vaughan-Shaw,Victoria Svinti...&Malcolm G. Dunlop.(2018).Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study..BMC medicine,16,(1)
MLA：
Yazhou He,et al."Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.".BMC medicine 16..1(2018):142
医学