title: Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: a GWAS data analysis.
abstract: BACKGROUND
  Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level.
  
  
  METHODS
  Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA).
  
  
  RESULTS
  After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10(-6)) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10(-4)) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10(-7)) at a false discovery rate of 6%.
  
  
  CONCLUSIONS
  Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets.
  
  
  CONCLUSIONS
  A gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.
authors.affiliation: Authors' Affiliations: Departments of Gastrointestinal Medical Oncology and Epidemiology, The University of Texas MD Anderson Cancer Center; Division of Biostatistics and Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas; Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain; Yale University School of Public Health, New Haven, Connecticut; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; National Institute for Public Health and the Environment (RIVM), Bilthoven and Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Samuel Lunenfeld Research Institute, Toronto General Hospital, University of Toronto, Toronto, Canada; Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, California; Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; International Agency for Research on Cancer, Lyon; Institut national de la santé et de la recherche medicale (INSERM), Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team; Univ. Paris Sud, UMRS 1018; IGR, F-94805, Villejuif, France; Division of Epidemiology, Public Health, and Primary Care, Imperial College London, London; School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Bureau of Epidemiologic Research, Academy of Athens; Hellenic Health Foundation, Athens, Greece; Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy; and Department 
authors.forename: Hongwei
authors.initials: H
authors.lastname: Tang
authors.forename: Peng
authors.initials: P
authors.lastname: Wei
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Duell
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.forename: Sara H
authors.initials: SH
authors.lastname: Olson
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holly
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.forename: Mazda
authors.initials: M
authors.lastname: Jenab
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Boutron-Ruault
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: Malin
authors.initials: M
authors.lastname: Sund
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Donghui
authors.initials: D
authors.lastname: Li
mesh_terms: D000368:Aged; D048909:Diabetes Complications / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000150:complications / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors