The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study

Robert Carreras-Torres; Mattias Johansson; Valérie Gaborieau; Philip Haycock; Kaitlin Wade; Caroline Relton; Richard Martin; George Davey Smith; Paul Brennan

doi:10.1093/jnci/djx012

The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study

Robert Carreras-Torres, Mattias Johansson, Valérie Gaborieau, Philip Haycock, Kaitlin Wade, Caroline Relton, Richard Martin, George Davey Smith, Paul Brennan

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

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Abstract

Background: Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer.

Methods: We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance and type 2 diabetes, in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk within a series of 7,110 pancreatic cancer cases and 7,264 controls using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4).

Results: A likelihood-based MR approach indicated a robust causal association of increasing body-mass index (BMI) with pancreatic cancer risk (OR [95%CI]= 1.34 [1.09-1.65]; for each standard deviation (SD) increase in BMI (4.6 Kg/m²
)). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR [95%CI]= 1.66 [1.05-2.63]; per SD (44.4 pmol/l)). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Assessment of potential unknown pleiotropic effects using a weighted-median approach and MR-Egger sensitivity analyses did not indicate that pleiotropy was an important source of bias.

Conclusions: Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.

Original language	English
Article number	djx012
Number of pages	9
Journal	Journal of the National Cancer Institute
Volume	109
Issue number	9
Early online date	28 Apr 2017
DOIs	https://doi.org/10.1093/jnci/djx012
Publication status	Published - 1 Sept 2017

Research Groups and Themes

ICEP

Keywords

Obesity
metabolic factors
pancreatic cancer
two-sample Mendelian randomization

UN SDGs

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

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10.1093/jnci/djx012

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NIHR BRC Nutrition
Ness, A. R. (Principal Investigator)
1/04/17 → 31/03/22
Project: Research, Parent
MRC UoB UNITE Unit - Programme 1
Davey Smith, G. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 2
Relton, C. L. (Principal Investigator) & Relton, C. L. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research

Professor George Davey Smith
- KZ.Davey-Smithbristol.acuk
- MRC Integrative Epidemiology Unit
- Bristol Medical School (PHS) - Professor of Clinical Epidemiology
Person: Academic , Member, Group lead
Professor Richard M Martin
- Richard.Martinbristol.acuk
- Bristol Medical School (PHS) - Associate Pro Vice Chancellor (Research & Innovation) & Professor of Clinical Epidemiology
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
- Cancer
Person: Academic , Member

Cite this

@article{e7f9496b93c249bd9659800c48eb6c64,

title = "The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study",

abstract = "Background: Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer. Methods: We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance and type 2 diabetes, in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk within a series of 7,110 pancreatic cancer cases and 7,264 controls using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Results: A likelihood-based MR approach indicated a robust causal association of increasing body-mass index (BMI) with pancreatic cancer risk (OR [95\%CI]= 1.34 [1.09-1.65]; for each standard deviation (SD) increase in BMI (4.6 Kg/m2 )). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR [95\%CI]= 1.66 [1.05-2.63]; per SD (44.4 pmol/l)). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Assessment of potential unknown pleiotropic effects using a weighted-median approach and MR-Egger sensitivity analyses did not indicate that pleiotropy was an important source of bias. Conclusions: Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.",

keywords = "Obesity, metabolic factors, pancreatic cancer, two-sample Mendelian randomization",

author = "Robert Carreras-Torres and Mattias Johansson and Val{\'e}rie Gaborieau and Philip Haycock and Kaitlin Wade and Caroline Relton and Richard Martin and \{Davey Smith\}, George and Paul Brennan",

year = "2017",

month = sep,

day = "1",

doi = "10.1093/jnci/djx012",

language = "English",

volume = "109",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "9",

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T1 - The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer

T2 - A Mendelian Randomization Study

AU - Carreras-Torres, Robert

AU - Johansson, Mattias

AU - Gaborieau, Valérie

AU - Haycock, Philip

AU - Wade, Kaitlin

AU - Relton, Caroline

AU - Martin, Richard

AU - Davey Smith, George

AU - Brennan, Paul

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background: Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer. Methods: We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance and type 2 diabetes, in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk within a series of 7,110 pancreatic cancer cases and 7,264 controls using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Results: A likelihood-based MR approach indicated a robust causal association of increasing body-mass index (BMI) with pancreatic cancer risk (OR [95%CI]= 1.34 [1.09-1.65]; for each standard deviation (SD) increase in BMI (4.6 Kg/m2 )). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR [95%CI]= 1.66 [1.05-2.63]; per SD (44.4 pmol/l)). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Assessment of potential unknown pleiotropic effects using a weighted-median approach and MR-Egger sensitivity analyses did not indicate that pleiotropy was an important source of bias. Conclusions: Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.

AB - Background: Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer. Methods: We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance and type 2 diabetes, in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk within a series of 7,110 pancreatic cancer cases and 7,264 controls using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Results: A likelihood-based MR approach indicated a robust causal association of increasing body-mass index (BMI) with pancreatic cancer risk (OR [95%CI]= 1.34 [1.09-1.65]; for each standard deviation (SD) increase in BMI (4.6 Kg/m2 )). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR [95%CI]= 1.66 [1.05-2.63]; per SD (44.4 pmol/l)). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Assessment of potential unknown pleiotropic effects using a weighted-median approach and MR-Egger sensitivity analyses did not indicate that pleiotropy was an important source of bias. Conclusions: Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.

KW - Obesity

KW - metabolic factors

KW - pancreatic cancer

KW - two-sample Mendelian randomization

U2 - 10.1093/jnci/djx012

DO - 10.1093/jnci/djx012

M3 - Article (Academic Journal)

C2 - 28954281

SN - 0027-8874

VL - 109

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 9

M1 - djx012

ER -

The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study

Abstract

Research Groups and Themes

Keywords

UN SDGs

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Projects

NIHR BRC Nutrition

MRC UoB UNITE Unit - Programme 1

MRC UoB UNITE Unit - Programme 2

Profiles

Professor George Davey Smith

Professor Richard M Martin

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