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 Hypponen, Peter Kraft, Douglas P. Kiel, Caroline Hayward, Archie Campbell, David Porteous, Katarina Vucic, Iva Kirac, Masa Filipovic & 7 others Sarah E. Harris, Ian J. Deary, Richard Houlston, Ian P. Tomlinson, Harry Campbell, Evropi Theodoratou, Malcolm G. Dunlop

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

LanguageEnglish
Article number142
JournalBMC Medicine
Volume16
Issue number1
DOIs
Publication statusPublished - 14 Aug 2018

Keywords

  • Colorectal cancer
  • Mendelian randomisation
  • Vitamin D

ASJC Scopus subject areas

  • Medicine(all)

Cite this

He, Yazhou ; Timofeeva, Maria ; Farrington, Susan M. ; Vaughan-Shaw, Peter ; Svinti, Victoria ; Walker, Marion ; Zgaga, Lina ; Meng, Xiangrui ; Li, Xue ; Spiliopoulou, Athina ; Jiang, Xia ; Hypponen, Elina ; Kraft, Peter ; Kiel, Douglas P. ; Hayward, Caroline ; Campbell, Archie ; Porteous, David ; Vucic, Katarina ; Kirac, Iva ; Filipovic, Masa ; Harris, Sarah E. ; Deary, Ian J. ; Houlston, Richard ; Tomlinson, Ian P. ; Campbell, Harry ; Theodoratou, Evropi ; Dunlop, Malcolm G. / Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk : A large Mendelian randomisation study. In: BMC Medicine. 2018 ; Vol. 16, No. 1.
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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 = "Colorectal cancer, Mendelian randomisation, Vitamin D",
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 Hypponen and Peter Kraft and Kiel, {Douglas P.} 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 = "8",
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doi = "10.1186/s12916-018-1119-2",
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He, Y, Timofeeva, M, Farrington, SM, Vaughan-Shaw, P, Svinti, V, Walker, M, Zgaga, L, Meng, X, Li, X, Spiliopoulou, A, Jiang, X, Hypponen, E, Kraft, P, Kiel, DP, 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, no. 1, 142. https://doi.org/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. / He, Yazhou; Timofeeva, Maria; Farrington, Susan M.; Vaughan-Shaw, Peter; Svinti, Victoria; Walker, Marion; Zgaga, Lina; Meng, Xiangrui; Li, Xue; Spiliopoulou, Athina; Jiang, Xia; Hypponen, Elina; Kraft, Peter; Kiel, Douglas P.; Hayward, Caroline; Campbell, Archie; Porteous, David; Vucic, Katarina; Kirac, Iva; Filipovic, Masa; Harris, Sarah E.; Deary, Ian J.; Houlston, Richard; Tomlinson, Ian P.; Campbell, Harry; Theodoratou, Evropi; Dunlop, Malcolm G.

In: BMC Medicine, Vol. 16, No. 1, 142, 14.08.2018.

Research output: Contribution to journalArticle

TY - JOUR

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

T2 - BMC Medicine

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 - Hypponen, Elina

AU - Kraft, Peter

AU - Kiel, Douglas P.

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 - Colorectal cancer

KW - Mendelian randomisation

KW - Vitamin D

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U2 - 10.1186/s12916-018-1119-2

DO - 10.1186/s12916-018-1119-2

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JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

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