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Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia

Tang H 1 , Jiang L 2 , Stolzenberg-Solomon RZ 3 , Arslan AA 4 , Beane Freeman LE 3 , Bracci PM 5 Show all authors , Brennan P 6 , Canzian F 7 , Du M 8 , Gallinger S 9 , Giles GG 10 , Goodman PJ 11 , Kooperberg C 12 , Le Marchand L 13 , Neale RE 14 , Shu XO 15 , Visvanathan K 16 , White E 17 , Zheng W 15 , Albanes D 3 , Andreotti G 3 , Babic A 18 , Bamlet WR 19 , Berndt SI 3 , Blackford A 20 , Bueno-de-Mesquita B 21 , Buring JE 2 , Campa D 22 , Chanock SJ 3 , Childs E 20 , Duell EJ 23 , Fuchs C 24 , Gaziano JM 25 , Goggins M 26 , Hartge P 3 , Hassam MH 1 , Holly EA 5 , Hoover RN 3 , Hung RJ 9 , Kurtz RC 27 , Lee IM 2 , Malats N 28 , Milne RL 10 , Ng K 18 , Oberg AL 19 , Orlow I 8 , Peters U 17 , Porta M 29 , Rabe KG 19 , Rothman N 3 , Scelo G 6 , Sesso HD 2 , Silverman DT 3 , Thompson IM 30 , Tjønneland A 31 , Trichopoulou A 32 , Wactawski-Wende J 33 , Wentzensen N 3 , Wilkens LR 13 , Yu H 13 , Zeleniuch-Jacquotte A 34 , Amundadottir LT 3 , Jacobs EJ 31 , Petersen GM 19 , Wolpin BM 18 , Risch HA 35 , Chatterjee N 36 , Klein AP 20 , Li D 37 , Kraft P 38 , Wei P 39

Affiliations 

  • 1 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
  • 2 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 3 Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland
  • 4 Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York
  • 5 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
  • 6 International Agency for Research on Cancer, Lyon, France
  • 7 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 8 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 9 Lunenfeld-Tanenbaum Research Institute, Sinai Health System and University of Toronto, Toronto, Ontario, Canada
  • 10 Division of Cancer Epidemiology, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 11 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 12 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 13 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
  • 14 Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 15 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 16 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 17 Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 18 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 19 Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
  • 20 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland
  • 21 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
  • 22 Department of Biology, University of Pisa, Pisa, Italy
  • 23 Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
  • 24 Yale Cancer Center, New Haven, Connecticut
  • 25 Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts
  • 26 Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland
  • 27 Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York
  • 28 Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain
  • 29 CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
  • 30 CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, Texas
  • 31 Department of Public Health, University of Copenhagen and Danish Cancer Society Research Center Diet, Genes and Environment, Copenhagen, Denmark
  • 32 Hellenic Health Foundation, World Health Organization Collaborating Center of Nutrition, Medical School, University of Athens, Athens, Greece
  • 33 Department of Epidemiology and Environmental Health, University of Buffalo, Buffalo, New York
  • 34 Department of Population Health, New York University School of Medicine, New York, New York
  • 35 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
  • 36 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 37 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. pwei2@mdanderson.org pkraft@hsph.harvard.edu dli@mdanderson.org
  • 38 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. pwei2@mdanderson.org pkraft@hsph.harvard.edu dli@mdanderson.org
  • 39 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. pwei2@mdanderson.org pkraft@hsph.harvard.edu dli@mdanderson.org
Cancer Epidemiol Biomarkers Prev, 2020 Sep;29(9):1784-1791.
PMID: 32546605 DOI: 10.1158/1055-9965.EPI-20-0275

Abstract

BACKGROUND: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.

METHODS: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.

RESULTS: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7).

CONCLUSIONS: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.

IMPACT: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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