Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization

Nonalcoholic fatty liver disease (NAFLD), a rapidly growing public health problem, affects approximately 30% of Americans (1). NAFLD is a spectrum of conditions ranging from simple steatosis (fatty liver) to nonalcoholic steatohepatitis to liver fibrosis and cirrhosis, and is considered a hepatic manifestation of metabolic abnormalities (1). NAFLD has been associated with a higher risk of pancreatic cancer (2), but the reported association between NAFLD and pancreatic cancer is not entirely consistent due partly to different definitions of NAFLD across studies (e.g., based on International Classification of Disease (ICD) codes, laboratory values of liver function, or hepatic imaging) and small numbers of pancreatic cancer cases (n = 24 to 72) included in these studies (2, 3). There is also the possibility that NAFLD may not be an independent risk factor for pancreatic cancer, but rather a reflection of underlying metabolic abnormalities, such as obesity and diabetes, which are known risk factors for pancreatic cancer.

Genetic factors explain up to 50% of individual variability in the risk of NAFLD (4) and may be a more robust means of exploring the temporal relationship between NAFLD and pancreatic cancer. Mendelian randomization (MR) allows for combining multiple genetic variants previously associated with NAFLD in genome-wide association studies (GWAS) to infer the causal relationship between NAFLD and pancreatic cancer. Using MR, we tested the hypothesis that inherited genetic predisposition to NAFLD is causally related to pancreatic cancer.

Data were obtained from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case Control Consortium (PanC4). To maximize statistical power, data from the three PanScan GWAS series (PanScan I, II, III) were combined (cases n = 5,090, controls n = 8,733) and analyzed separately from PanC4 (cases n = 4,163, controls n = 3,792). Details of the two consortia, including genetic data quality control checks have been published (5). All participants were of European ancestry.

The data may be made available to researchers upon request to the PanScan and the PanC4.

Descriptive characteristics of the participants are presented in Supplementary Tables S9–S10. During initial evaluation of individual SNPs, only one NAFLD-related SNP was associated with pancreatic cancer, ABO-rs687621, P = 1.15 × 10⁻¹⁷ for PanScan and 1.31 × 10⁻¹³ for PanC4 (Supplementary Tables S1, S2, S5, and S6). The MR analyses did not show an association between genetically predicted NAFLD and risk of pancreatic cancer in the fully adjusted (Figs. 1–2) or minimally adjusted (Supplementary Figs. S1–S2) models.

To our knowledge, this is the first study to examine the relationship between genetic predisposition to NAFLD and risk of pancreatic cancer. We did not find an association between NAFLD heritability and pancreatic cancer risk. Although some nongenetic studies have reported an association between NAFLD and pancreatic cancer, those studies were limited by small numbers of pancreatic cancer cases. In addition to using data from two consortia, we employed four different MR approaches to evaluate the relationship between NAFLD and pancreatic cancer, with each producing null results. Our findings thus suggest that the reported association between NAFLD and pancreatic cancer likely reflects the presence of metabolic perturbations among PC cases. This is supported by data indicating that a majority (∼75%) of individuals with NAFLD have a concurrent diagnosis of diabetes (8), a well-established risk factor for pancreatic cancer. A limitation of our study is that all participants were of European ancestry and the findings cannot be generalized to individuals from other ethnicities.

X. Shu reports grants from NCI during the conduct of the study. P.M. Bracci reports grants from NIH/NCI during the conduct of the study. M. Du reports grants from NCI, Geoffrey Beene Foundation; other support from Arnold and Arlene Goldstein Family Foundation, David M. Rubenstein Center for Pancreatic Cancer Research, Gastrointestinal Endoscopy Research Fund; and grants from Society of MSKCC during the conduct of the study. G.G. Giles reports grants from National Health and Medical Research Council during the conduct of the study. R.E. Neale reports grants from National Health and Medical Research Council during the conduct of the study; grants from Viatris; and other support from Viatris outside the submitted work. J.E. Buring reports grants from NIH during the conduct of the study. C.S. Fuchs reports other support from Genentech/Roche outside the submitted work. I. Lee reports grants from NIH during the conduct of the study. A.L. Oberg reports grants from NCI during the conduct of the study. J. Wactawski-Wende reports grants from NIH/NHLBI during the conduct of the study. X. Wang reports other support from Flatiron Health, Inc. and other support from Roche outside the submitted work. A. Zeleniuch-Jacquotte reports grants from NIH/NCI during the conduct of the study. P. Kraft reports grants from NIH during the conduct of the study. H.A. Risch reports grants from NCI, NIH during the conduct of the study. No disclosures were reported by the other authors.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

S.D. King: Formal analysis, writing–original draft, writing–review and editing. S. Veliginti: Data curation, visualization, writing–original draft, writing–review and editing. M.C. Brouwers: Methodology. Z. Ren: Methodology. W. Zheng: Data curation, writing–review and editing. V.W. Setiawan: Writing–review and editing. L.R. Wilkens: Writing–review and editing. X. Shu: Writing–review and editing. A.A. Arslan: Data curation, writing–review and editing. L.E. Beane Freeman: Data curation, writing–review and editing. P.M. Bracci: Data curation, writing–review and editing. F. Canzian: Data curation, writing–review and editing. M. Du: Data curation, writing–review and editing. S.J. Gallinger: Data curation, writing–review and editing. G.G. Giles: Data curation, writing–review and editing. P.J. Goodman: Writing–review and editing. C.A. Haiman: Writing–review and editing. M. Kogevinas: Writing–review and editing. C. Kooperberg: Writing–review and editing. L. Le Marchand: Data curation, writing–review and editing. R.E. Neale: Writing–review and editing. K. Visvanathan: Writing–review and editing. E. White: Writing–review and editing. D. Albanes: Writing–review and editing. G. Andreotti: Data curation, writing–review and editing. A. Babic: Writing–review and editing. S.I. Berndt: Writing–review and editing. L.K. Brais: Writing–review and editing. P. Brennan: Writing–review and editing. J.E. Buring: Writing–review and editing. K.G. Rabe: Data curation, writing–review and editing. W.R. Bamlet: Data curation, writing–review and editing. S.J. Chanock: Writing–review and editing. C.S. Fuchs: Writing–review and editing. J. Gaziano: Writing–review and editing. E.L. Giovannucci: Data curation, writing–review and editing. T. Hackert: Data curation, writing–review and editing. M.M. Hassan: Writing–review and editing. V. Katzke: Writing–review and editing. R.C. Kurtz: Writing–review and editing. I. Lee: Writing–review and editing. N. Malats: Writing–review and editing. N. Murphy: Writing–review and editing. A.L. Oberg: Writing–review and editing. I. Orlow: Writing–review and editing. M. Porta: Writing–review and editing. F.X. Real: Writing–review and editing. N. Rothman: Writing–review and editing. H.D. Sesso: Writing–review and editing. D.T. Silverman: Data curation, writing–review and editing. I.M. Thompson: Writing–review and editing. J. Wactawski-Wende: Writing–review and editing. X. Wang: Writing–review and editing. N. Wentzensen: Writing–review and editing. H. Yu: Writing–review and editing. A. Zeleniuch-Jacquotte: Writing–review and editing. K. Yu: Writing–review and editing. B.M. Wolpin: Data curation, writing–review and editing. E.J. Duell: Writing–review and editing. D. Li: Data curation, writing–review and editing. R.J. Hung: Writing–review and editing. S. Perdomo: Data curation, writing–review and editing. M.L. McCullough: Writing–review and editing. N.D. Freedman: Writing–review and editing. A.V. Patel: Writing–review and editing. U. Peters: Writing–review and editing. E. Riboli: Writing–review and editing. M. Sund: Writing–review and editing. A. Tjønneland: Writing–review and editing. J. Zhong: Writing–original draft. S.K. Van Den Eeden: Writing–review and editing. P. Kraft: Writing–review and editing. H.A. Risch: Data curation, writing–review and editing. L.T. Amundadottir: Data curation, writing–review and editing. A.P. Klein: Data curation, writing–review and editing. R.Z. Stolzenberg-Solomon: Data curation, writing–review and editing. S.O. Antwi: Conceptualization, resources, formal analysis, supervision, funding acquisition, investigation, methodology, writing–original draft, project administration, writing–review and editing.

This project has been funded in whole or in part with Federal funds from the NCI, NIH, under NCI contract no. 75N910D00024 (to L. T. Amundadottir). The Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria (to G. G. Giles). The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383 and by infrastructure provided by Cancer Council Victoria (to G.G. Giles). Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the Australian Cancer Database. The Women's Health Study (WHS) was supported with funding from the NCI (CA047988, CA182913) and the National Heart, Lung and Blood Institute (HL043851, HL080467, and HL099355, to J.E. Buring). The study was also supported by NCI funding (K01 CA237875, to S.O. Antwi). The late Dr. Gloria M. Petersen contributed substantially to the conception and design of this study but did not live to see the completion of this work. We, therefore, dedicate this work to Dr. Petersen. We remember and celebrate Dr. Petersen for her passion for science, mentorship to scores of early-career investigators, her inclusive intellect, and her kind and generous spirit. We also thank all the pancreatic cancer patients and cancer-free controls who contributed biospecimen and data that made this work possible. The authors acknowledge the research contributions of the Cancer Genomics Research Laboratory for their expertise, execution, and support of this research in the areas of project planning, wet laboratory processing of specimens, and bioinformatics analysis of the data.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.