Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Sep 1;32(9):1265-1269.
doi: 10.1158/1055-9965.EPI-23-0453.

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

Sontoria D King #  1 , Swathi Veliginti #  2 , Martijn C G J Brouwers  3   4 , Zhewen Ren  3   4 , Wei Zheng  5 , Veronica W Setiawan  6 , Lynne R Wilkens  7 , Xiao-Ou Shu  5 , Alan A Arslan  8 , Laura E Beane Freeman  9 , Paige M Bracci  10 , Federico Canzian  11 , Mengmeng Du  12 , Steven J Gallinger  13   14 , Graham G Giles  15   16   17 , Phyllis J Goodman  18 , Christopher A Haiman  6 , Manolis Kogevinas  19 , Charles Kooperberg  20 , Loic LeMarchand  7   7 , Rachel E Neale  21 , Kala Visvanathan  22   23 , Emily White  24 , Demetrius Albanes  9 , Gabriella Andreotti  9 , Ana Babic  25 , Sonja I Berndt  9 , Lauren K Brais  25 , Paul Brennan  26 , Julie E Buring  27   28 , Kari G Rabe  29 , William R Bamlet  29 , Stephen J Chanock  9 , Charles S Fuchs  30   31   32 , J Michael Gaziano  28   33 , Edward L Giovannucci  27   34   35 , Thilo Hackert  36 , Manal M Hassan  37 , Verena Katzke  38 , Robert C Kurtz  39 , I-Min Lee  27   28 , Núria Malats  40 , Neil Murphy  41 , Ann L Oberg  29 , Irene Orlow  12 , Miquel Porta  42 , Francisco X Real  43 , Nathaniel Rothman  9 , Howard D Sesso  27   28 , Debra T Silverman  9 , Ian M Thompson  44 , Jean Wactawski-Wende  45 , Xiaoliang Wang  24 , Nicolas Wentzensen  9 , Herbert Yu  7 , Anne Zeleniuch-Jacquotte  46 , Kai Yu  9 , Brian M Wolpin  25 , Eric J Duell  47 , Donghui Li  37 , Rayjean J Hung  48 , Sandra Perdomo  26 , Marjorie L McCullough  49 , Neal D Freedman  9 , Alpa V Patel  49 , Ulrike Peters  20 , Elio Riboli  27   28 , Malin Sund  50 , Anne Tjønneland  51 , Jun Zhong  9 , Stephen K Van Den Eeden  52   53 , Peter Kraft  27 , Harvey A Risch  54 , Laufey T Amundadottir  9 , Alison P Klein  22   23   55 , Rachael Z Stolzenberg-Solomon  9 , Samuel O Antwi  2   56
Affiliations

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

Sontoria D King et al. Cancer Epidemiol Biomarkers Prev. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest: The authors declare no potential conflicts of interest related to this work.

Figures

Figure 1:
Figure 1:. Results from Mendelian randomization analyses.
The first plot (A) shows results for the PanScan cohort derived from logistic regression analyses using four different instrumental variables (polymorphism sets) with four different Mendelian randomization methods to assess the relationship between genetic heritability of NAFLD and PC risk. The second plot (B) shows results for the PanC4 samples obtained from logistic regression analyses using four separate instrumental variables with four Mendelian randomization methods. Each of the logistic regression models adjusted for age, sex, the top five principal components of genetic ancestry, personal history of diabetes, and smoking history. Abbreviations: cALT, chronically elevated serum alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; PanC4, Pancreatic Cancer Case-Control Consortium; PanScan, Pancreatic Cancer Cohort Consortium; PC, pancreatic cancer; MR, Mendelian randomization; SNP, single nucleotide polymorphism.
Figure 2:
Figure 2:. Plot of genetically predicted NAFLD and risk for PC.
The first plot (A) shows results from the PanScan data (68 SNPs), and the second plot (B) shows results from the PanC4 data (67 SNPs). The following MR methods were used: inverse variance weighting (light blue line), MR Egger (deep blue line), penalized weighted median (dashed green line), and simple median (pink line). Abbreviations: NAFLD, nonalcoholic fatty liver disease; PanC4, Pancreatic Cancer Case-Control Consortium; PanScan, Pancreatic Cancer Cohort Consortium; MR, Mendelian randomization; SNP, single nucleotide polymorphism.
See this image and copyright information in PMC

References

    1. Cotter TG, Rinella M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology 2020;158(7):1851–64 doi 10.1053/j.gastro.2020.01.052. - DOI - PubMed
    1. Allen AM, Hicks SB, Mara KC, Larson JJ, Therneau TM. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - A longitudinal cohort study. J Hepatol 2019;71(6):1229–36 doi 10.1016/j.jhep.2019.08.018. - DOI - PMC - PubMed
    1. Kim GA, Lee HC, Choe J, Kim MJ, Lee MJ, Chang HS, et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol 2017. doi 10.1016/j.jhep.2017.09.012. - DOI - PubMed
    1. Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, et al. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015;149(7):1784–93 doi 10.1053/j.gastro.2015.08.011. - DOI - PMC - PubMed
    1. Klein AP, Wolpin BM, Risch HA, Stolzenberg-Solomon RZ, Mocci E, Zhang M, et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun 2018;9(1):556 doi 10.1038/s41467-018-02942-5. - DOI - PMC - PubMed

Publication types

MeSH terms