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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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    • "The association between these two diseases could also be explained via pleiotropy, whereby specific genetic variants affect both type 2 diabetes and prostate cancer risk, independently [4]. Several genes recently identified in type 2 diabetes GWA studies have also been found to be associated with prostate cancer risk [3] [5] [6] [7]. "
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    ABSTRACT: AIMS: Epidemiological evidence shows that diabetes is associated with a reduced risk of prostate cancer. The objective of this study was to identify genes that may contribute to both type 2 diabetes and prostate cancer outcomes and the biological pathways these diseases may share. METHODS: The Atherosclerosis Risk in Communities (ARIC) Study is a population-based prospective cohort study in four U.S. communities that included a baseline examination in 1987-89 and three follow-up exams at three year intervals. Participants were 45-64 years old at baseline. We conducted a genomewide association (GWA) study of incident type 2 diabetes in males, summarized variation across genetic loci into a polygenic risk score, and determined if that diabetes risk score was also associated with incident prostate cancer in the same study population. Secondarily we conducted a separate GWA study of prostate cancer, performed a pathway analysis of both type 2 diabetes and prostate cancer, and qualitatively determined if any of the biochemical pathways identified were shared between the two outcomes. RESULTS: We found that the polygenic risk score for type 2 diabetes was not statistically significantly associated with prostate cancer. The pathway analysis also found no overlap between pathways associated with type 2 diabetes and prostate cancer. However, it did find that the growth hormone signaling pathway was statistically significantly associated with type 2 diabetes (p=0.0001). CONCLUSION: The inability of this study to find an association between type 2 diabetes polygenic risk scores with prostate cancer or biological pathways in common suggests that shared genetic variants may not contribute significantly to explaining shared etiology.
    International Journal of Molecular Epidemiology and Genetics 01/2013; 4(1):49-60.
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    • "[24], which is in agreement with our results. This hypothesis may also be supported by recent studies reporting an association between increased T2D genetic susceptibility and reduced prostate cancer risk [25,26]. In our study, we found no significant relationship with the ‘T2D’-risk allele and cancer mortality, although our sample size was probably too small to detect this association. "
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    ABSTRACT: The genomic region at 9p21 chromosome near the CDKN2A/CDKN2B genes is associated with type 2 diabetes(T2D) and cardiovascular disease(CVD). The effect of the 9p21 locus on long-term mortality in patients with T2D has yet to be determined. We examined three single nucleotide polymorphisms (SNPs) on 9p21, consistently and independently associated with T2D (rs10811661) or CVD (rs10757278, rs2383206), in relation to the risk of total and cardiovascular mortality in diabetic patients. We also aimed to replicate the previously observed interaction between rs2383206 and glycemic control on mortality. Genotypes for three SNPs were determined in 914 individuals from a prospective cohort of T2D patients of Dutch origin. Associations with mortality were assessed using Cox proportional hazard analyses. After a median follow-up of 9.5 years, 358 out of 914 patients had died. The hazard ratio (HR) for total mortality among individuals homozygous for the T2D-risk allele of rs10811661 compared to non-homozygous individuals was 0.74(95%CI 0.59-0.93). For the carriers of both CVD-risk alleles of rs10757278, the HR for total mortality was 1.31(95%CI 1.01-1.70). We found a significant interaction between rs2383206 and HbA1c on mortality, which was higher among patients with two CVD-risk alleles in the two lowest HbA1c tertiles (HR 1.68(95%CI 1.08-2.63); HR 1.48(95%CI 1.01-2.18). In conclusion, common variants on 9p21 were associated with mortality in patients with T2D in a Dutch population. The T2D SNP was inversely associated with mortality, while the CVD SNP increased the risk for mortality. We confirmed a possible, although different, synergistic relationship between HbA1c and rs2383206 on total mortality.
    Cardiovascular Diabetology 11/2012; 11(1):138. DOI:10.1186/1475-2840-11-138 · 3.71 Impact Factor
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    ABSTRACT: Recent genome-wide association studies enlarged our knowledge about the genetic background of type 2 diabetes. This review provides an overview of the role of these novel genetic findings for the pathophysiology, prediction and treatment of type 2 diabetes. The genetic susceptibility to type 2 diabetes appears to be determined by many common variants in multiple gene loci with low effect sizes. Although at least 36 diabetes-associated genes were identified, only about 10% of the heritability of type 2 diabetes can be explained. Most of the discovered gene variants have been linked to beta-cell dysfunction rather than insulin resistance, which might challenge established thinking of type 2 diabetes as a predominant disorder of insulin action. Genetic data can lead to statistically significant, but not to clinically relevant contributions to risk prediction for type 2 diabetes. Nevertheless, preliminary evidence suggests interactions between genotypes and response to lifestyle changes or drug treatment. Future studies need to target the issue of hidden heritability and to detect the causal gene variants within the identified gene loci. Improved understanding of the genetic contribution to type 2 diabetes may then help addressing the questions whether genotyping is useful to predict individual diabetes risk, identifies individual responsiveness to preventive and therapeutic interventions or at least allows for breaking down type 2 diabetes into smaller, clinically meaningful subtypes.
    European Journal of Clinical Investigation 12/2010; 41(6):679-92. DOI:10.1111/j.1365-2362.2010.02454.x · 2.83 Impact Factor
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