title: Vitamin D metabolic pathway genes and pancreatic cancer risk.
abstract: Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Hannah
authors: H
authors: Arem
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Kai
authors: K
authors: Yu
authors: Information Management Systems, Inc., Calverton, Maryland, United States of America.
authors: Xiaoqin
authors: X
authors: Xiong
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Kristin
authors: K
authors: Moy
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Neal D
authors: ND
authors: Freedman
authors: Yale School of Public Health/Yale Cancer Center, New Haven, Connecticut, United States of America.
authors: Susan T
authors: ST
authors: Mayne
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Demetrius
authors: D
authors: Albanes
authors: Departments of Population Health, Obstetrics and Gynecology (Obs/Gyn) and Environmental Medicine, New York University, New York, New York, United States of America.
authors: Alan A
authors: AA
authors: Arslan
authors: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors: Melissa
authors: M
authors: Austin
authors: Department of Epidemiology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors: William R
authors: WR
authors: Bamlet
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Laura
authors: L
authors: Beane-Freeman
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors: Paige
authors: P
authors: Bracci
authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Federico
authors: F
authors: Canzian
authors: Dalla Lana School of Public Health, University of Toronto; Prevention and Cancer Control, Cancer Care Ontario Toronto, Ontario, Canada.
authors: Michelle
authors: M
authors: Cotterchio
authors: Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
authors: Eric J
authors: EJ
authors: Duell
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
authors: Steve
authors: S
authors: Gallinger
authors: Cancer Epidemiology Centre, Cancer Council Victoria and Centre for MEGA Epidemiology, School of Population Health, the University of Melbourne, Melbourne, Australia.
authors: Graham G
authors: GG
authors: Giles
authors: Departments of Oncology, Pathology and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Michael
authors: M
authors: Goggins
authors: Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States of America.
authors: Phyllis J
authors: PJ
authors: Goodman
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Patricia
authors: P
authors: Hartge
authors: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Manal
authors: M
authors: Hassan
authors: MD Mercy, Baltimore, Maryland, United States of America.
authors: Kathy
authors: K
authors: Helzlsouer
authors: Department of Preventative Medicine, School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Brian
authors: B
authors: Henderson
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors: Elizabeth A
authors: EA
authors: Holly
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Robert
authors: R
authors: Hoover
authors: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, United States of America.
authors: Eric J
authors: EJ
authors: Jacobs
authors: GroupHealth Research Institute, Seattle, Washington, United States of America.
authors: Aruna
authors: A
authors: Kamineni
authors: MD Mercy, Baltimore, Maryland, United States of America.
authors: Alison
authors: A
authors: Klein
authors: Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States of America.
authors: Eric
authors: E
authors: Klein
authors: University of Hawaii Cancer Center, Manoa, Hawaii, United States of America.
authors: Laurence N
authors: LN
authors: Kolonel
authors: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Donghui
authors: D
authors: Li
authors: Molecular Pathology Program, Spanish National Cancer Research Center, Madrid, Spain.
authors: Núria
authors: N
authors: Malats
authors: National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland.
authors: Satu
authors: S
authors: Männistö
authors: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, United States of America.
authors: Marjorie L
authors: ML
authors: McCullough
authors: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors: Sara H
authors: SH
authors: Olson
authors: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors: Irene
authors: I
authors: Orlow
authors: Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States of America.
authors: Ulrike
authors: U
authors: Peters
authors: Department of Epidemiology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors: Gloria M
authors: GM
authors: Petersen
authors: Hospital del Mar Institute of Medical Research (IMIM), and School of Medicine, Barcelona Spain.
authors: Miquel
authors: M
authors: Porta
authors: Cancer Epidemiology Centre, Cancer Council Victoria and Centre for MEGA Epidemiology, School of Population Health, the University of Melbourne, Melbourne, Australia.
authors: Gianluca
authors: G
authors: Severi
authors: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Xiao-Ou
authors: XO
authors: Shu
authors: MD Mercy, Baltimore, Maryland, United States of America.
authors: Kala
authors: K
authors: Visvanathan
authors: Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States of America.
authors: Emily
authors: E
authors: White
authors: University of Hawaii Cancer Center, Manoa, Hawaii, United States of America.
authors: Herbert
authors: H
authors: Yu
authors: Departments of Population Health, Obstetrics and Gynecology (Obs/Gyn) and Environmental Medicine, New York University, New York, New York, United States of America.
authors: Anne
authors: A
authors: Zeleniuch-Jacquotte
authors: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Wei
authors: W
authors: Zheng
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Geoffrey S
authors: GS
authors: Tobias
authors: Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors: Dennis
authors: D
authors: Maeder
authors: Westat, Rockville, Maryland, United States of America.
authors: Michelle
authors: M
authors: Brotzman
authors: Yale School of Public Health/Yale Cancer Center, New Haven, Connecticut, United States of America.
authors: Harvey
authors: H
authors: Risch
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Joshua N
authors: JN
authors: Sampson
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors: Rachael Z
authors: RZ
authors: Stolzenberg-Solomon
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014807:Vitamin D / Q000097:blood* / Q000235:genetics; D014809:Vitamin D-Binding Protein / Q000235:genetics; D014815:Vitamins / Q000097:blood / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D014809:Vitamin D-Binding Protein; D014815:Vitamins; D014807:Vitamin D