Abstract
Long-term type 2 diabetes is a known risk factor for pancreatic cancer (PC). We hypothesized that genetic variants in glucose metabolism modify individual susceptibility to PC, especially those associated with diabetes. We retrospectively genotyped 26 single-nucleotide polymorphisms of 5 glucose metabolism genes: glucokinase (GCK), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose phosphate isomerase (GPI), hexokinase 2 (HK2), and O-linked N-acetylglucosamine transferase (OGT) in a case-control study of PC conducted at MD Anderson during 2004 to 2010. Initial genotyping was conducted in 706 patients with PC and 706 cancer-free controls by using the Sequenom method. A HK2 genotype (R844K) with low frequency of homozygous variant was further examined in additional 948 patients and 476 controls. In the combined set of 1,654 cases and 1,182 controls, we showed a significant association of the HK2 R844K GA/AA genotype with reduced PC risk (OR = 0.78; 95% CI, 0.64-0.94; P = 0.009) and a significant interaction with diabetes (P(interaction) < 0.001). The HK2 R844K GA/AA genotype was associated with a reduced risk of PC among nondiabetic individuals (OR = 0.68; 95% CI, 0.56-0.83) but with increased risk among diabetic patients (OR = 3.69; 95% CI, 2.34-5.82). These risk associations remained statistically significant when the analysis was restricted to whites or after exclusion of recent onset diabetes. No significant main effect of other genes or significant interaction of genotype with other risk factors was observed. The findings show a potential role of HK2 gene, alone or in interaction with diabetes, in modifying the risk of PC.