Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Yazhou He; Maria Timofeeva; Susan M. Farrington; Peter Vaughan-Shaw; Victoria Svinti; Marion Walker; Lina Zgaga; Xiangrui Meng; Xue Li; Athina Spiliopoulou; Xia Jiang; Elina Hyppönen; Peter Kraft; Douglas P. Kiel; The SUNLIGHT Consortium; Caroline Hayward; Archie Campbell; David Porteous; Katarina Vucic; Iva Kirac; Masa Filipovic; Sarah E. Harris; Ian J. Deary; Richard Houlston; Ian P. Tomlinson; Harry Campbell; Evropi Theodoratou; Malcolm G. Dunlop

doi:10.1186/s12916-018-1119-2

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Yazhou He, Maria Timofeeva, Susan M. Farrington, Peter Vaughan-Shaw, Victoria Svinti, Marion Walker, Lina Zgaga, Xiangrui Meng, Xue Li, Athina Spiliopoulou, Xia Jiang, Elina Hyppönen, Peter Kraft, Douglas P. Kiel, The SUNLIGHT Consortium, Caroline Hayward, Archie Campbell, David Porteous, Katarina Vucic, Iva KiracMasa Filipovic, Sarah E. Harris, Ian J. Deary, Richard Houlston, Ian P. Tomlinson, Harry Campbell, Evropi Theodoratou, Malcolm G. Dunlop

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	142
Journal	BMC Medicine
Volume	16
DOIs	https://doi.org/10.1186/s12916-018-1119-2
Publication status	Published - 14 Aug 2018

Keywords

Case-Control Studies
Colorectal Neoplasms/etiology
Female
Humans
Male
Mendelian Randomization Analysis/methods
Middle Aged
Risk Factors
Vitamin D/adverse effects

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https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1119-2

1 Active
5 Finished

Colorectal cancer reduction through risk stratification of screening, follow-up and treatment
Theodoratou, E.
UK-based charities
1/05/17 → 30/04/23
Project: Research
Integrative Genomics in Colorectal Cancer Susceptibility:Developing risk reducing interventions through understanding biology
Dunlop, M., Campbell, H., Farrington, S. & Theodoratou, E.
UK-based charities
1/01/16 → 31/05/21
Project: Research
Stratifying Resilience and Depression Longitudinally
McIntosh, A., Deary, I., Evans, K., Haley, C. & Porteous, D.
UK-based charities
1/01/15 → 30/06/21
Project: Research

Malcolm Dunlop
- Deanery of Molecular, Genetic and Population Health Sciences - Chair of Coloproctology
- Edinburgh Cancer Research Centre
Person: Academic: Research Active

Cite this

He, Y., Timofeeva, M., Farrington, S. M., Vaughan-Shaw, P., Svinti, V., Walker, M., Zgaga, L., Meng, X., Li, X., Spiliopoulou, A., Jiang, X., Hyppönen, E., Kraft, P., Kiel, D. P., The SUNLIGHT Consortium, Hayward, C., Campbell, A., Porteous, D., Vucic, K., ... Dunlop, M. G. (2018). Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study. BMC Medicine, 16, [142]. https://doi.org/10.1186/s12916-018-1119-2

@article{82a5fdf627874e63a726e21ad0fcfe5b,

title = "Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study",

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.",

keywords = "Case-Control Studies, Colorectal Neoplasms/etiology, Female, Humans, Male, Mendelian Randomization Analysis/methods, Middle Aged, Risk Factors, Vitamin D/adverse effects",

author = "Yazhou He and Maria Timofeeva and Farrington, {Susan M.} and Peter Vaughan-Shaw and Victoria Svinti and Marion Walker and Lina Zgaga and Xiangrui Meng and Xue Li and Athina Spiliopoulou and Xia Jiang and Elina Hypp{\"o}nen and Peter Kraft and Kiel, {Douglas P.} and {The SUNLIGHT Consortium} and Caroline Hayward and Archie Campbell and David Porteous and Katarina Vucic and Iva Kirac and Masa Filipovic and Harris, {Sarah E.} and Deary, {Ian J.} and Richard Houlston and Tomlinson, {Ian P.} and Harry Campbell and Evropi Theodoratou and Dunlop, {Malcolm G.}",

year = "2018",

month = aug,

day = "14",

doi = "10.1186/s12916-018-1119-2",

language = "English",

volume = "16",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central",

}

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, The 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 2018, 'Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study', BMC Medicine, vol. 16, 142. https://doi.org/10.1186/s12916-018-1119-2

TY - JOUR

T1 - Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk

T2 - a large Mendelian randomisation study

AU - He, Yazhou

AU - Timofeeva, Maria

AU - Farrington, Susan M.

AU - Vaughan-Shaw, Peter

AU - Svinti, Victoria

AU - Walker, Marion

AU - Zgaga, Lina

AU - Meng, Xiangrui

AU - Li, Xue

AU - Spiliopoulou, Athina

AU - Jiang, Xia

AU - Hyppönen, Elina

AU - Kraft, Peter

AU - Kiel, Douglas P.

AU - The SUNLIGHT Consortium

AU - Hayward, Caroline

AU - Campbell, Archie

AU - Porteous, David

AU - Vucic, Katarina

AU - Kirac, Iva

AU - Filipovic, Masa

AU - Harris, Sarah E.

AU - Deary, Ian J.

AU - Houlston, Richard

AU - Tomlinson, Ian P.

AU - Campbell, Harry

AU - Theodoratou, Evropi

AU - Dunlop, Malcolm G.

PY - 2018/8/14

Y1 - 2018/8/14

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - Colorectal Neoplasms/etiology

KW - Female

KW - Humans

KW - Male

KW - Mendelian Randomization Analysis/methods

KW - Middle Aged

KW - Risk Factors

KW - Vitamin D/adverse effects

U2 - 10.1186/s12916-018-1119-2

DO - 10.1186/s12916-018-1119-2

M3 - Article

C2 - 30103784

VL - 16

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

M1 - 142

ER -

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Abstract

Keywords

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Projects

Colorectal cancer reduction through risk stratification of screening, follow-up and treatment

Integrative Genomics in Colorectal Cancer Susceptibility:Developing risk reducing interventions through understanding biology

Stratifying Resilience and Depression Longitudinally

Profiles

Malcolm Dunlop

Cite this