Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study

Andrei-Emil Constantinescu; Caroline J Bull; Nicholas Jones; Ruth Mitchell; Kimberley Burrows; Niki Dimou; Stéphane Bézieau; Hermann Brenner; Daniel D Buchanan; Mauro D'Amato; Mark A Jenkins; Victor Moreno; Rish K Pai; Caroline Y Um; Emily White; Neil Murphy; Marc Gunter; Nicholas J Timpson; Jeroen R Huyghe; Emma E Vincent

doi:10.1002/ijc.34691

Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study

Andrei-Emil Constantinescu^*, Caroline J Bull, Nicholas Jones, Ruth Mitchell, Kimberley Burrows, Niki Dimou, Stéphane Bézieau, Hermann Brenner, Daniel D Buchanan, Mauro D'Amato, Mark A Jenkins, Victor Moreno, Rish K Pai, Caroline Y Um, Emily White, Neil Murphy, Marc Gunter, Nicholas J Timpson, Jeroen R Huyghe, Emma E Vincent

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

Original language	English
Pages (from-to)	94-103
Number of pages	10
Journal	International Journal of Cancer
Volume	154
Issue number	1
Early online date	14 Aug 2023
DOIs	https://doi.org/10.1002/ijc.34691
Publication status	E-pub ahead of print - 14 Aug 2023

Bibliographical note

Funding Information:
Andrei‐Emil Constantinescu acknowledges funding from grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. Nicholas J. Timpson is the PI of the Avon Longitudinal Study of Parents and Children (Medical Research Council & Wellcome Trust 217065/Z/19/Z) and is supported by the University of Bristol NIHR Biomedical Research Centre (BRC‐1215‐2001). Nicholas J. Timpson acknowledges funding from the Wellcome Trust (202802/Z/16/Z). Emma E. Vincent, Caroline J. Bull, Niki Dimou and Nicholas J. Timpson acknowledge funding by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Nicholas J. Timpson, Emma E. Vincent, Caroline J. Bull and Ruth Mitchell work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4) and the University of Bristol. Emma E. Vincent and Caroline J. Bull are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). Jeroen R. Huyghe acknowledges funding by the National Cancer Institute at the U.S. National Institutes of Health (R21CA230486). This work was also supported by the Elizabeth Blackwell Institute for Health Research, the University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (ISSF 204813/Z/16/Z). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

Publisher Copyright:
© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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1 Finished
1 Active

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research
IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Using genetic data to determine the effect of routinely measured blood cell traits on disease
Constantinescu, A. (Author), Vincent, E. (Supervisor), Timpson, N. (Supervisor), Bull, C. (Supervisor) & Dayan, C. (Supervisor), 3 Oct 2023
Student thesis: Doctoral Thesis › Doctor of Philosophy (PhD)

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Constantinescu, A.-E., Bull, C. J., Jones, N., Mitchell, R., Burrows, K., Dimou, N., Bézieau, S., Brenner, H., Buchanan, D. D., D'Amato, M., Jenkins, M. A., Moreno, V., Pai, R. K., Um, C. Y., White, E., Murphy, N., Gunter, M., Timpson, N. J., Huyghe, J. R., & Vincent, E. E. (2023). Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study. International Journal of Cancer, 154(1), 94-103. Advance online publication. https://doi.org/10.1002/ijc.34691

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title = "Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study",

abstract = "Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.",

author = "Andrei-Emil Constantinescu and Bull, {Caroline J} and Nicholas Jones and Ruth Mitchell and Kimberley Burrows and Niki Dimou and St{\'e}phane B{\'e}zieau and Hermann Brenner and Buchanan, {Daniel D} and Mauro D'Amato and Jenkins, {Mark A} and Victor Moreno and Pai, {Rish K} and Um, {Caroline Y} and Emily White and Neil Murphy and Marc Gunter and Timpson, {Nicholas J} and Huyghe, {Jeroen R} and Vincent, {Emma E}",

note = "Funding Information: Andrei‐Emil Constantinescu acknowledges funding from grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. Nicholas J. Timpson is the PI of the Avon Longitudinal Study of Parents and Children (Medical Research Council & Wellcome Trust 217065/Z/19/Z) and is supported by the University of Bristol NIHR Biomedical Research Centre (BRC‐1215‐2001). Nicholas J. Timpson acknowledges funding from the Wellcome Trust (202802/Z/16/Z). Emma E. Vincent, Caroline J. Bull, Niki Dimou and Nicholas J. Timpson acknowledge funding by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Nicholas J. Timpson, Emma E. Vincent, Caroline J. Bull and Ruth Mitchell work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4) and the University of Bristol. Emma E. Vincent and Caroline J. Bull are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). Jeroen R. Huyghe acknowledges funding by the National Cancer Institute at the U.S. National Institutes of Health (R21CA230486). This work was also supported by the Elizabeth Blackwell Institute for Health Research, the University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (ISSF 204813/Z/16/Z). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. Publisher Copyright: {\textcopyright} 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",

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Constantinescu, A-E, Bull, CJ, Jones, N, Mitchell, R, Burrows, K, Dimou, N, Bézieau, S, Brenner, H, Buchanan, DD, D'Amato, M, Jenkins, MA, Moreno, V, Pai, RK, Um, CY, White, E, Murphy, N, Gunter, M, Timpson, NJ, Huyghe, JR & Vincent, EE 2023, 'Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study', International Journal of Cancer, vol. 154, no. 1, pp. 94-103. https://doi.org/10.1002/ijc.34691

TY - JOUR

T1 - Circulating white blood cell traits and colorectal cancer risk

T2 - A Mendelian randomisation study

AU - Constantinescu, Andrei-Emil

AU - Bull, Caroline J

AU - Jones, Nicholas

AU - Mitchell, Ruth

AU - Burrows, Kimberley

AU - Dimou, Niki

AU - Bézieau, Stéphane

AU - Brenner, Hermann

AU - Buchanan, Daniel D

AU - D'Amato, Mauro

AU - Jenkins, Mark A

AU - Moreno, Victor

AU - Pai, Rish K

AU - Um, Caroline Y

AU - White, Emily

AU - Murphy, Neil

AU - Gunter, Marc

AU - Timpson, Nicholas J

AU - Huyghe, Jeroen R

AU - Vincent, Emma E

N1 - Funding Information: Andrei‐Emil Constantinescu acknowledges funding from grant MR/N0137941/1 for the GW4 BIOMED MRC DTP, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. Nicholas J. Timpson is the PI of the Avon Longitudinal Study of Parents and Children (Medical Research Council & Wellcome Trust 217065/Z/19/Z) and is supported by the University of Bristol NIHR Biomedical Research Centre (BRC‐1215‐2001). Nicholas J. Timpson acknowledges funding from the Wellcome Trust (202802/Z/16/Z). Emma E. Vincent, Caroline J. Bull, Niki Dimou and Nicholas J. Timpson acknowledge funding by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Nicholas J. Timpson, Emma E. Vincent, Caroline J. Bull and Ruth Mitchell work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 and MC_UU_00011/4) and the University of Bristol. Emma E. Vincent and Caroline J. Bull are supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009). Jeroen R. Huyghe acknowledges funding by the National Cancer Institute at the U.S. National Institutes of Health (R21CA230486). This work was also supported by the Elizabeth Blackwell Institute for Health Research, the University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (ISSF 204813/Z/16/Z). The funders of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. Publisher Copyright: © 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

PY - 2023/8/14

Y1 - 2023/8/14

N2 - Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

AB - Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.

U2 - 10.1002/ijc.34691

DO - 10.1002/ijc.34691

M3 - Article (Academic Journal)

C2 - 37578112

SN - 0020-7136

VL - 154

SP - 94

EP - 103

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 1

ER -

Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study

Abstract

Bibliographical note

Research Groups and Themes

UN SDGs

Access to Document

Handle.net

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Student theses

Using genetic data to determine the effect of routinely measured blood cell traits on disease

Cite this