Original Article A polymorphism in the glucokinase gene that raises plasma fasting glucose, rs1799884, is associated with diabetes mellitus and prostate cancer: findings from a population-based, case-control study (the ProtecT study)
Ali S. Murad, George Davey Smith, Sarah J. Lewis, Angela Cox, Jenny L. Donovan, David E. Neal, Freddie C. Hamdy, Richard M. Martin
Department of Social Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK; MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Oakfield House, Bristol, BS8 2BN, UK; Institute for Cancer Studies, University of Sheffield, Sheffield S10 2RX , UK; Department of Oncology, University of Cambridge, Box 279 (S4), Addenbrooke’s Hospital, Cambridge, CB2 8RP, UK; Nuffield Department of Surgery, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Received February 15, 2010, accepted March 24, 2010, available online: April 1, 2010
Abstract: Epidemiological studies have identified a positive association between prostate cancer and recent onset type 2 diabetes mellitus but an increasingly inverse association with greater duration of type 2 diabetes. The mechanisms underlying these paradoxical associations are not clear. A single nucleotide polymorphism in the glucokinase gene, rs1799884, is associated with higher circulating plasma fasting glucose and with an increased risk of type 2 diabetes. We report a case-control study nested within the population-based Prostate testing for cancer and Treatment (ProtecT) study ISRCTN20141297. Men aged 50-69 years based around 9 UK cities were invited for a prostate specific antigen (PSA) test between June 2002 and November 2006. 1,551 cases and 2,993 controls were genotyped. We observed suggestive evidence for a positive association between the AA variant rs1799884 and PSAdetected prostate cancer (ORAA v GG= 1.40, 95% CI= 0.95 to 2.07). There was little evidence that this effect was greater for more advanced stage / grade cancers (ORAA v GG= 1.78, 95% CI= 0.99 to 3.21) versus less advanced cancers (ORAA v GG= 1.23, 95% CI= 0.77 to 1.94) (p for interaction = 0.33). The rs1799884 genotype was not associated with PSA concentration, suggesting that any effect on prostate cancer risk is not attributable to PSA detection bias. Our results provide suggestive evidence for a link between a genotype associated with type 2 diabetes mellitus and PSA-detected prostate cancer. We hypothesize that hyperglycaemia may be important in mediating this relationship. (IJMEG1002004).
Key words: Single nucleotide polymorphisms, glucokinase, GCK, rs1799884, prostate cancer, diabetes, insulin, case-control study, prostate specific antigen