Type 2 diabetes risk variants and colorectal cancer risk: The Multiethnic Cohort and PAGE studies
ABSTRACT Diabetes has been positively associated with the risk of colorectal cancer. This study investigated whether recently established risk variants for diabetes also have effects on colorectal cancer.
19 single nucleotide repeats (SNPs) associated with type 2 diabetes in genome-wide association studies were tested in a case-control study of 2011 colorectal cancer cases and 6049 controls nested in the Multiethnic Cohort study as part of the Population Architecture using Genomics and Epidemiology (PAGE) initiative. ORs and 95% CIs were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex and race/ethnicity. Permutation testing was conducted to correct for multiple hypothesis testing.
Four type 2 diabetes SNPs were associated with colorectal cancer risk: rs7578597 (THADA), rs864745 (JAZF1), rs5219 (KCNJ11) and rs7961581 (TSPAN8, LGR5). The strongest association was for the rs7578597 (THADA) Thr1187Ala missense polymorphism (P(trend)=0.004 adjusted for multiple testing), with the high risk allele for colorectal cancer being the low risk allele for diabetes. Similar patterns of associations were seen with further adjustment for diabetes status and body mass index. The association of diabetes status with colorectal cancer risk was somewhat weakened after adjustment for these SNPs.
The findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through mechanisms different from those for diabetes.
- SourceAvailable from: Brian Giunta
[Show abstract] [Hide abstract]
- "These discrepancies could be due to differences in size and composition of the investigated populations. Recently, the type 2 diabetes SNP rs7961581 (TSPAN8/LGR5) was found to be associated with colorectal cancer risk , but there was no evidence for this association in our database. Surprisingly, we registered a lower variant allele frequency assigned to SNP rs10879303 in colorectal cancer patients compared to healthy individuals, which could be a possible hint at a protective function of this SNP against colorectal cancer. "
ABSTRACT: Microglia become activated in humans subsequent to infection with HIV, and uncontrolled brain inflammation plays a key role in neuronal injury and and cognitive dysfunction during HIV infection. Various studies have shown a deleterious role for the HIV regulatory protein Tat in the development and maintenance of HIV-associated neurocognitive disorders (HAND). One cell surface receptor implicated in inhibiting microglial activation is the protein-tyrosine phosphatase (PTP), CD45. It is especially effective at inhibiting microglial activation because its action takes place far upstream from proinflammatory intracellular signaling mediators. To investigate the possible role of CD45 in microglial responsiveness to HIV-1 Tat protein, we treated BV-2 microglia with a tyrosine phosphatase inhibitor [potassium bisperoxo (1, 10-phenanthroline) oxovanadate (phen), 5 μM] and HIV-1 Tat protein (700ng/ml). We found a synergistic pro-inflammatory microglial activation as supported by tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β) release, both of which were dependent on p44/42 mitogen-activated protein kinase (MAPK) activation. Stimulation of microglial CD45 by anti-CD45 antibody markedly inhibited these Tat or Tat/Phen effects via attenuation of p44/42 MAPK, suggesting CD45 negatively regulates microglial activation. As a validation of these findings in vivo, brains from transgenic mice deficient for CD45 through complete genetic ablation, or by CNS delivery of CD45shRNA, demonstrate markedly increased production of TNF-α 24 hours after intracerebroventricular injection of HIV-Tat protein (5μg/mouse) compared to control mice. This increased microglial activation was accompanied by astrogliosis and a significant loss of cortical neurons due to apoptosis in CD45 deficient animals. These results suggest therapeutic agents that activate CD45 PTP signaling may be effective in suppressing microglial activation associated with HAND.American Journal of Translational Research 01/2012; 4(3):302-15. · 3.23 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Epidemiologic studies have found evidence of an inverse association between diabetes status and prostate cancer risk. We explored the hypothesis that common genetic variation may explain, in part, the inverse association between diabetes and prostate cancer. We tested 17 diabetes risk variants for association with prostate cancer risk in a prostate cancer case-control study of 2,746 cases and 3,317 controls from five racial/ethnic groups in the Multiethnic Cohort (MEC) study. After adjustment for multiple testing, none of the alleles were statistically significantly associated with prostate cancer risk. Aggregate scores that sum the risk alleles were also not significantly associated with risk. We did not find evidence of association of this set of diabetes risk alleles with prostate cancer. Resequencing and fine-mapping of the loci for diabetes and prostate cancer that were identified by genome-wide association studies are necessary to understand any genetic contribution for the inverse association between these common diseases.Cancer Epidemiology Biomarkers & Prevention 08/2011; 20(9):1979-81. DOI:10.1158/1055-9965.EPI-11-0019 · 4.32 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Morphological and clinical heterogeneity of advanced colorectal cancer is probably caused by genetic variability in putative cancer stem cell genes, including Lgr5. Here, we investigated 23 variants of the Lgr5 gene in normal tissue, primary tumors, lymph node metastases and distant metastases of stage III and stage IV colorectal cancer patients. These data were compared to results of immunohistochemical Lgr5 expression analysis and to prognostic clinical parameters. No differences were found comparing germline and somatic Lgr5 genotype in primary tumors, but additional Lgr5 gene alterations could be demonstrated in lymph node and distant metastases. Significant negative correlation was seen between Lgr5 allelic variation and Lgr5 protein expression (p=0.0394), which mainly can be attributed to the negative influence of non-coding Lgr5 gene variations on Lgr5 protein expression (p=0.0166). Lgr5 gene variants could be found more frequently in primary tumors of stage III patients with increased time to recurrence, in distant metastases of patients with better survival and in lymph node metastases of patients with poorer survival compared to patients with Lgr5 wild type in primary and metastatic tissues, respectively. However, the analytic power of these prognostic data was low due to small sample size in the investigated groups. In conclusion, our data indicate that Lgr5 allelic variation affect Lgr5 protein expression in colorectal carcinomas. The somatic Lgr5 genotype seems to be relatively stable in primary tumors, but becomes vulnerable during the metastatic process of colorectal cancer. This instability has possibly prognostic importance, which has to be further evaluated by large cohort studies.American Journal of Translational Research 01/2012; 4(3):279-90. · 3.23 Impact Factor