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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention

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Research Articles

A Phenome-Wide Mendelian Randomization Study of Pancreatic Cancer Using Summary Genetic Data

Ryan J. Langdon, Rebecca C. Richmond, Gibran Hemani, Jie Zheng, Kaitlin H. Wade, Robert Carreras-Torres, Mattias Johansson, Paul Brennan, Robyn E. Wootton, Marcus R. Munafo, George Davey Smith, Caroline L. Relton, Emma E. Vincent, Richard M. Martin and Philip Haycock
Ryan J. Langdon
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Rebecca C. Richmond
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Gibran Hemani
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Jie Zheng
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Kaitlin H. Wade
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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  • ORCID record for Kaitlin H. Wade
Robert Carreras-Torres
Biomarkers and Susceptibility Unit, IDIBELL-Bellvitge Biomedical Research Institute, Barcelona, Spain.
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  • ORCID record for Robert Carreras-Torres
Mattias Johansson
Section of Genetics, International Agency for Research on Cancer (IARC), Lyon, France.
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Paul Brennan
Section of Genetics, International Agency for Research on Cancer (IARC), Lyon, France.
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Robyn E. Wootton
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
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Marcus R. Munafo
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
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George Davey Smith
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Caroline L. Relton
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Emma E. Vincent
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Richard M. Martin
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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Philip Haycock
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, United Kingdom.
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  • For correspondence: philip.haycock@bristol.ac.uk
DOI: 10.1158/1055-9965.EPI-19-0036 Published December 2019
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Abstract

Background: The 5-year mortality rate for pancreatic cancer is among the highest of all cancers. Greater understanding of underlying causes could inform population-wide intervention strategies for prevention. Summary genetic data from genome-wide association studies (GWAS) have become available for thousands of phenotypes. These data can be exploited in Mendelian randomization (MR) phenome-wide association studies (PheWAS) to efficiently screen the phenome for potential determinants of disease risk.

Methods: We conducted an MR-PheWAS of pancreatic cancer using 486 phenotypes, proxied by 9,124 genetic variants, and summary genetic data from a GWAS of pancreatic cancer (7,110 cancer cases, 7,264 controls). ORs and 95% confidence intervals per 1 SD increase in each phenotype were generated.

Results: We found evidence that previously reported risk factors of body mass index (BMI; 1.46; 1.20–1.78) and hip circumference (1.42; 1.21–1.67) were associated with pancreatic cancer. We also found evidence of novel associations with metabolites that have not previously been implicated in pancreatic cancer: ADpSGEGDFXAEGGGVR*, a fibrinogen-cleavage peptide (1.60; 1.31–1.95), and O-sulfo-l-tyrosine (0.58; 0.46–0.74). An inverse association was also observed with lung adenocarcinoma (0.63; 0.54–0.74).

Conclusions: Markers of adiposity (BMI and hip circumference) are potential intervention targets for pancreatic cancer prevention. Further clarification of the causal relevance of the fibrinogen-cleavage peptides and O-sulfo-l-tyrosine in pancreatic cancer etiology is required, as is the basis of our observed association with lung adenocarcinoma.

Impact: For pancreatic cancer, MR-PheWAS can augment existing risk factor knowledge and generate novel hypotheses to investigate.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

  • Cancer Epidemiol Biomarkers Prev 2019;28:2070–8

  • Received January 14, 2019.
  • Revision received March 29, 2019.
  • Accepted July 10, 2019.
  • Published first July 17, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Epidemiology Biomarkers & Prevention: 28 (12)
December 2019
Volume 28, Issue 12
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A Phenome-Wide Mendelian Randomization Study of Pancreatic Cancer Using Summary Genetic Data
Ryan J. Langdon, Rebecca C. Richmond, Gibran Hemani, Jie Zheng, Kaitlin H. Wade, Robert Carreras-Torres, Mattias Johansson, Paul Brennan, Robyn E. Wootton, Marcus R. Munafo, George Davey Smith, Caroline L. Relton, Emma E. Vincent, Richard M. Martin and Philip Haycock
Cancer Epidemiol Biomarkers Prev December 1 2019 (28) (12) 2070-2078; DOI: 10.1158/1055-9965.EPI-19-0036

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A Phenome-Wide Mendelian Randomization Study of Pancreatic Cancer Using Summary Genetic Data
Ryan J. Langdon, Rebecca C. Richmond, Gibran Hemani, Jie Zheng, Kaitlin H. Wade, Robert Carreras-Torres, Mattias Johansson, Paul Brennan, Robyn E. Wootton, Marcus R. Munafo, George Davey Smith, Caroline L. Relton, Emma E. Vincent, Richard M. Martin and Philip Haycock
Cancer Epidemiol Biomarkers Prev December 1 2019 (28) (12) 2070-2078; DOI: 10.1158/1055-9965.EPI-19-0036
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