Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization
Authors: King Sontoria D. , Veliginti Swathi , Brouwers Martijn C.G.J. , Ren Zhewen , Zheng Wei , Setiawan Veronica W. , Wilkens Lynne R. , Shu Xiao-Ou , Arslan Alan A. , Beane Freeman Laura E. , Bracci Paige M. , Canzian Federico , Du Mengmeng , Gallinger Steven J. , Giles Graham G. , Goodman Phyllis J. , Haiman Christopher A. , Kogevinas Manolis , Kooperberg Charles , LeMarchand Loic , Neale Rachel E. , Visvanathan Kala , White Emily , Albanes Demetrius , Andreotti Gabriella , Babic Ana , Berndt Sonja I. , Brais Lauren K. , Brennan Paul , Buring Julie E. , Rabe Kari G. , Bamlet William R. , Chanock Stephen J. , Fuchs Charles S. , Gaziano J. Michael , Giovannucci Edward L. , Hackert Thilo , Hassan Manal M. , Katzke Verena , Kurtz Robert C. , Lee I.-Min , Malats Núria , Murphy Neil , Oberg Ann L. , Orlow Irene , Porta Miquel , Real Francisco X. , Rothman Nathaniel , Sesso Howard D. , Silverman Debra T. , Thompson Ian M. , Wactawski-Wende Jean , Wang Xiaoliang , Wentzensen Nicolas , Yu Herbert , Zeleniuch-Jacquotte Anne , Yu Kai , Wolpin Brian M. , Duell Eric J. , Li Donghui , Hung Rayjean J. , Perdomo Sandra , McCullough Marjorie L. , Freedman Neal D. , Patel Alpa V. , Peters Ulrike , Riboli Elio , Sund Malin , Tjønneland Anne , Zhong Jun , Van Den Eeden Stephen K. , Kraft Peter , Risch Harvey A. , Amundadottir Laufey T. , Klein Alison P. , Stolzenberg-Solomon Rachael Z. , Antwi Samuel O. 
Published: June 2023

Abstract

Background:
There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer.

Methods:
Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes.

Results:
No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88–1.22; MR-Egger OR, 0.89; 95% CI, 0.65–1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90–1.27; MR-Egger OR, 0.93; 95% CI, 0.67–1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample.

Conclusions:
Genetic predisposition to NAFLD is not associated with pancreatic cancer risk.

Impact:
Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.