Diabetes Genes and Prostate Cancer in the Atherosclerosis Risk in Communities Study

Human Genetics Center and Division of Epidemiology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 02/2010; 19(2):558-65. DOI: 10.1158/1055-9965.EPI-09-0902
Source: PubMed

ABSTRACT There is a known inverse association between type 2 diabetes (T2D) and prostate cancer (PrCa) that is poorly understood. Genetic studies of the T2D-PrCa association may provide insight into the underlying mechanisms of this association. We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms from genome-wide association studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D single nucleotide polymorphisms from pre-genome-wide association studies (in ADRB2, CAPN10, SLC2A2, and UCP2). From 1987 to 2000, there were 397 incident PrCa cases among 6,642 men ages 45 to 64 years at baseline. We used race-adjusted Cox proportional hazards models to estimate associations between PrCa and increasing number of T2D risk-raising alleles. PrCa was positively associated with the CAPN10 rs3792267 G allele [hazard ratio (HR) 1.20; 95% confidence interval (CI), 1.00-1.44] and inversely associated with the SLC2A2 rs5400 Thr110 allele (HR, 0.85; 95% CI, 0.72, 1.00), the UCP2 rs660339 Val55 allele (HR, 0.84; 95% CI, 0.73, 0.97) and the IGF2BP2 rs4402960 T allele (HR, 0.79; 95% CI, 0.61-1.02; blacks only). The TCF7L2 rs7903146 T allele was inversely associated with PrCa using a dominant genetic model (HR, 0.79; 95% CI, 0.65-0.97). Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology.

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    ABSTRACT: BACKGROUND. Variation in transcription factor 7-like 2 (TCF7L2), the strongest genetic risk factor for type 2 diabetes (T2D), may play a role in prostate cancer (PCa) depending on lifestyle factors. The aims of this study were to determine if TCF7L2 rs7903146 is associated with risk of PCa and if the association is modified by lifestyle factors independently of T2D status. METHODS. We prospectively followed 8,558 men in the Malmo Diet and Cancer Study from baseline 1991-1996 until end of 2009. Cox regression models were used to assess the association between rs7903146 T2D-risk allele (T) and PCa. Effect modification by incident T2D status, fasting glucose levels, dietary, and lifestyle risk factors were tested. RESULTS. During follow-up 855 incident PCa cases were registered. We observed a nonsignificant tendency for the TCF7L2 variant to associate with higher risk of PCa, which was unaffected by adjustment for incident T2D (HR=1.24; 95% CI: 0.96, 1.60; P=0.079) but more pronounced among subjects who developed T2D (HR=1.91, 95% CI: 0.88, 4.14; P=0.064). In a sub-sample of hyperglycemic men we observed an increased risk of PCa among T-allele carriers (HR=2.72, 95% CI: 1.22, 6.04; P=0.014; P-interaction=0.056). T-allele carriers with higher number of lifestyle risk factors had an increased risk of PCa (P-interaction=0.006). CONCLUSIONS. We found no independent association between TCF7L2 rs7903146 and PCa risk. However, among hyperglycemic men we observed that the risk allele may increase risk of PCa. The association between rs7903146 and PCa risk may also be modified by lifestyle factors. (C) 2014 Wiley Periodicals, Inc.
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