1. Promises, Delivery, and Challenges of Inflammatory Bowel Disease Risk Gene Discovery 
Steven R. Brant 
Clinical Gastroenterology and Hepatology 
Volume 11, Issue 1, Pages (January 2013)
DOI: /j.cgh
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2. Figure 1
Plot of association results of European (CEU) and African American (AA) CD cases and controls genotyped at high density using the Immunochip, showing the ZNF365 chromosome 10 locus. Each circle represents an SNP position on the x-axis according to location on chromosome 10 in megabases (Mb). The height of the circles correlates with the significance of a given SNP association (by using χ2 test) with CD [−log10 (P value) left margin y-axis]. Results shown from analysis of 2000 CEU CD cases and 2000 controls (from the National Institute of Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium [NIDDK-IBDGC]) (lower panel) and in 500 AA CD cases and 1500 controls (top panel). The genes that map to the region are noted by horizontal bars just above the x-axis with blocks on these bars denoting coding exons, arrows representing the direction of RNA transcription, and the gene symbols written just above (in italicized capital letters). The solid blue line represents the recombination rate across the genome (y-axis right margin). The ZNF365 locus was first identified in a European ancestry GWAS at SNP rs (black wide arrow) in an intergenic region between ZNF365 and ADO and EGR2 genes. The SNP most significantly associated with CD in the higher density International IBD Genetics Consortium Immunochip genotyping study was rs and is the same maximally associated SNP for the CEU and AA NIDDK-IBDGC data sets shown here (red arrowheads and purple shaded circles). Alleles on SNPs represented by green circles, and to a lesser extent light blue circles, are more strongly co-inherited with the alleles on rs , having higher r2 coefficient measures of LD (r2 box on left side). Immunochip genotyping also shows a separate set of SNPs located close to one another with strong evidence of association; the top associated SNP for this group (in LD with each other but minimally with rs ) is indicated by the black arrowhead. These SNPs are located proximal to ADO and EGR2 genes. Localization may be helped by genotyping the more diverse AA population, which shows lower LD of SNPs in relation to rs but also shows an SNP with slightly lower association evidence as rs but on the opposite side of EGR2 (arrow). The top associated SNPs are all noncoding and might be associated by an effect on regulation of expression of perhaps any 1 of the 3 most proximal genes or even the RTKN2 gene (symbol within blue rectangle), an outstanding candidate that affects CD4+ T-cell apoptosis. (NOTE: For interpretation of the color references in this legend, please see the online version of this figure at
Clinical Gastroenterology and Hepatology  , 22-26DOI: ( /j.cgh )
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3. Figure 2
Numerous genes within IBD loci (asterisks) influence Th17 cells: RORC is the gene for RORγt, the master transcription factor for Th17 differentiation.2 ICOSLG encodes the ligand B7RP1 that enhances IL-17A production via ICOS. IL12B encodes the p40 subunit of IL-12 and IL-23 cytokines. IL-12 via IL-12 receptor (heterodimer generated from IL12RB2 and IL12RB1) and acting through JAK2 and STAT4, can inhibit Th17 differentiation or induce Th17/Th1 cells (producing both IL17A and interferon-γ).2 IL-23, production stimulated by prostaglandin activation via PTGER4 encoded receptor on antigen-presenting cells (APC), binds to its receptor, composed of a heterodimer encoded by IL23R and IL12RB1 genes. IL23R binding activates JAK2 phosphorylation of the transcription factor STAT3, which then can activate IL-17 promoter transcription. IL12RB1 receptor subunit also can activate TYK2 phosphorylation of STAT3. APC cells produce the tumor necrosis factor–like molecule TL1A, encoded by TNFSF15. TL1A via DR3 is important for differentiation and proliferation of Th17 cells. Th17 cells produce a number of cytokines, including IL-21. The G-protein coupled chemokine receptor 6 (CCR6) is important for Th17 migration and undergoes (autocrine) stimulation by its ligand CCL20. Note that while these IBD risk genes help define Th17 effector functions, many of these genes are also important for the function of other cell populations involved in IBD pathophysiology.
Clinical Gastroenterology and Hepatology  , 22-26DOI: ( /j.cgh )
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