There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.

The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P ¼ 0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P ¼ 0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P ¼ 0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway -in this case, TLR4 and its signaling molecule TIRAP -plays a role in susceptibility to IBD.

Dose-escalated conformal radiotherapy is increasingly being used to radically treat prostate cancer with encouraging results and minimal long-term toxicity, yet little is known regarding the response of normal or malignant prostate cells to ionizing radiation (IR). To clarify the basis for cell killing during prostate cancer radiotherapy, we determined the IR-induced expression of several apoptotic-(bax, bcl-2, survivin and PARP) and G1-cell cycle checkpoint-(p53 and p21 WAF1/Cip1 ) related proteins, in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145 and PC-3; all epithelial) prostate cells. For these experiments, we chose doses ranging from 2 to 10 Gy, to be representative of the 1.8 -2 Gy daily clinical fractions given during curative radiotherapy and the 8 -10 Gy single doses given in palliative radiotherapy. We observed that IR-induced bax and p21 WAF1/Cip1 protein expression were attenuated selectively in normal stromal and epithelial cell cultures, yet maintained their p53-dependency in malignant cell lines. For each cell culture, we also determined total apoptotic and overall radiation cell kill using a short-term nuclear morphologic assay and a long-term clonogenic survival assay, respectively. Clonogenic survival, as measured by the surviving fraction at 2 Gy (SF2), ranged from 0.05 (PrEC) to 0.55 (DU-145), suggesting that malignant prostate cells are more radioresistant than normal prostate cells, for this series. IR-induced apoptotic cell kill was minimal (less than 6% cell after a dose of 10 Gy at times of 24 -96 h) and was not dose-dependent. Furthermore, apoptotic kill was not correlated with either molecular apoptotic response or clonogenic cell kill. Using a flow cytometric proliferation assay with the PrSC (stromal) and representative cultures, we observed that a senescent-like phenotype (SLP) emerges within a sub-population of cells post-irradiation that is non-clonogenic. Terminal growth arrest was dose-responsive at 96 h following irradiation and associated with long-term expression of both p21 WAF1/Cip1 and p16 INK4a genes. Future strategies for prostate radiotherapy prediction or novel treatments should additionally focus on terminal growth arrest as an important endpoint in prostate cancer therapy.

Although the general association of the inflammatory bowel disease (IBD) 5 region on chromosome 5q31 to Crohn's disease (CD) has been replicated repeatedly, the identity of the precise causal variant within the region remains unknown. A recent report proposed polymorphisms in solute carrier family 22, member 4 (SLC22A4) organic cation transporter 1(OCTN1) and solute carrier family 22, member 5 (SLC22A5) (OCTN2) as responsible for the IBD5 association, but definitive, large-sample comparison of those polymorphisms with others known to be in strong linkage disequilibrium was not performed. We evaluated 1879 affected offspring and parents ascertained by a North American IBD Genetics Consortium for six IBD5 tag single nucleotide polymorphisms (SNPs) to evaluate association localization and ethnic and subphenotypic specificity. We confirm association to the IBD5 region (best SNP IGR2096a_1/rs12521868, Po0.0005) and show this association to be exclusive to the non-Jewish (NJ) population (P ¼ 0.00005) (risk allele undertransmitted in Ashkenazi Jews). Using Phase II HapMap data, we demonstrate that there are a set of polymorphisms, spanning genes from prolyl 4-hydroxylase (P4HA2) through interferon regulatory factor 1 (IRF1) with equivalent statistical evidence of association to the reported SLC22A4 variant and that each, by itself, could entirely explain the IBD5 association to CD. Additionally, the previously reported SLC22A5 SNP is rejected as the potential causal variant. No specificity of association was seen with respect to disease type and location, and a modest association to ulcerative colitis is also observed. We confirm the importance of IBD5 to CD susceptibility, demonstrate that the locus may play a role in NJ individuals only,

IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype-phenotype studies.