TY - JOUR
T1 - Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer
T2 - A GWAS data analysis
AU - Tang, Hongwei
AU - Wei, Peng
AU - Duell, Eric J.
AU - Risch, Harvey A.
AU - Olson, Sara H.
AU - Bueno-De-Mesquita, H. Bas
AU - Gallinger, Steven
AU - Holly, Elizabeth A.
AU - Petersen, Gloria M.
AU - Bracci, Paige M.
AU - McWilliams, Robert R.
AU - Jenab, Mazda
AU - Riboli, Elio
AU - Tjønneland, Anne
AU - Boutron-Ruault, Marie Christine
AU - Kaaks, Rudolf
AU - Trichopoulos, Dimitrios
AU - Panico, Salvatore
AU - Sund, Malin
AU - Peeters, Petra H.M.
AU - Khaw, Kay Tee
AU - Amos, Christopher I.
AU - Li, Donghui
PY - 2014/1
Y1 - 2014/1
N2 - 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. Impact: A gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 23(1); 98-106.
AB - 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. Impact: A gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 23(1); 98-106.
UR - http://www.scopus.com/inward/record.url?scp=84892692797&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892692797&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-13-0437-T
DO - 10.1158/1055-9965.EPI-13-0437-T
M3 - Article
C2 - 24136929
AN - SCOPUS:84892692797
SN - 1055-9965
VL - 23
SP - 98
EP - 106
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 1
ER -