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Background We aimed to identify a model of clinical and genetic risk factors through hypothesis-free search across genome that can predict the surgical recurrence risk after the first abdominal surgery in CD patients. Materials and Methods Two independent inflammatory bowel disease (IBD) cohort studies were used to derive and validate the genetic risk profile. The study subjects were genotyped using Illumina Immunochip custom genotyping array. Surgical recurrence was defined as having the second or more abdominal bowel resections after the first abdominal surgery at the time of study enrollment; nonsurgical recurrence was defined as having no further abdominal resection after the first abdominal surgery. Results Among 372 CD patients who had at least 1 abdominal surgery at the study enrollment, 132 (35.5%) had subsequent surgical recurrence after their first abdominal surgery, and 240 (64.5%) required no subsequent abdominal surgery at the end of follow up. Among clinical factors, multivariable analysis showed that history of immunomodulatory use (odds ratio [OR], 3.96; P = 0.002) and early era of CD first surgery (OR, 1.12; P = 1.01E-04) remained significant. Genotypic association tests identified a genome-wide significant locus rs2060886 in TCF4 at chr18q21.2 associated with surgical recurrence risk (OR, dom, 4.10 [2.37–7.11]; P = 4.58E-08). Conclusions Novel genetic locus rs2060886 in TCF4 was associated with surgical recurrence risk at genome-wide significance level among CD patients after their first abdominal surgery. Early era of CD first intestinal surgery predicts higher surgical recurrence risk. These results suggest that genetic variants may help guide the CD management strategy in patients at the highest risk of repeated abdominal surgeries.

Background It is important to identify patients with inflammatory bowel disease [IBD] refractory to anti-tumour necrosis factor [TNF] therapy, to avoid potential adverse effects and to adopt different treatment strategies. We aimed to identify and validate clinical and genetic factors to predict anti-TNF response in patients with IBD. Materials and Methods Mayo Clinic and Washington University IBD genetic association study cohorts were used as discovery and replicate datasets, respectively. Clinical factors included sex, age at diagnosis, disease duration and phenotype, disease location, bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy. Results Of 474 patients with IBD treated with anti-TNF therapy, 41 [8.7%] were refractory to therapy and 433 [91.3%] had response. Multivariate analysis showed history of immunomodulator use (odds ratio 10.2, p = 8.73E-4) and bowel resection (odds ratio 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents. Among genetic loci, two [rs116724455 in TNFSF4/18, rs2228416 in PLIN2] were successfully replicated and another four [rs762787, rs9572250, rs144256942, rs523781] with suggestive evidence were found. An exploratory risk model predictability [area under the curve] increased from 0.72 [clinical predictors] to 0.89 after adding genetic predictors. Through identified clinical and genetic predictors, we constructed a preliminary anti-TNF refractory score to differentiate anti-TNF non-responders (mean [standard deviation] score, 5.49 [0.99]) from responders (2.65 [0.39]; p = 4.33E-23). Conclusions Novel and validated genetic loci, including variants in TNFSF, were found associated with anti-TNF response in patients with IBD. Future validation of the exploratory risk model in a large prospective cohort is warranted.

Background and aims Ulcerative colitis (UC) is a form of inflammatory bowel disease, and antibodies against tumor necrosis factor (anti-TNF) are used for treatment. Many patients are refractory or lose response to anti-TNF, and predicting response would be an extremely valuable clinical tool. Unlike most biomarkers, cytokines directly mediate inflammation, and their measurement may predict the likelihood of response or no response. Methods Serum samples were obtained from 49 UC patients before infliximab infusions, and levels of 17 cytokines were measured using a multiplex assay. The Fisher linear discriminant analysis (FLDA) was applied to the cytokine values to predict which patients would respond to infliximab. "Response" was defined as clinical remission after the third infusion, and "no response" was defined as lack of remission after the third infusion. Results The Fisher linear discriminant analysis model identified a subset of seven predictor cytokines: TNF-α, IL-12, IL-8, IL-2, IL-5, IL1-β, and IFN-γ. The obtained canonical coefficients enabled to calculate discriminant scores as linear combinations of the cytokines; model classified thepatients as responders and nonresponders with a sensitivity of 84.2% and a specificity of 93.3%. Overall, the yield of the FLDA model was 89.8% of the total 49 patients. Conclusions An unbiased, statistically derived, predictive model based on measurement of serum cytokines before therapy may predict a positive or negative outcome from the administration of anti-TNF to UC patients. Because accurately measuring cytokines is simple and inexpensive, the model may be a valuable new tool to complement other laboratory parameters used in the management of IBD patients.

Gastrointestinal (GI) amyloidosis is rare and has varying clinical and endoscopic presentations. In this case series, we present three patients with primary systemic amyloid-light chain (AL) amyloidosis with GI involvement and complications of GI bleeding. We also provide a brief review of the literature, including clinical presentation, endoscopic findings, pathology, and management of GI amyloidosis. The endoscopic findings of GI amyloidosis can vary, including friable mucosa with erosions, ulcers, and submucosal hematomas or mucosal thickening with polypoid protrusions. The endoscopic findings may correlate with the pathologic deposition of amyloid fibrils. Treatment of GI amyloidosis is generally focused on management of the underlying condition and supportive care. Gastroenterologists should be familiar with the endoscopic findings as they may be the first suggestion of disease and allow for definitive diagnosis.

Since the discovery of the first Crohn's disease (CD) gene NOD2 in 2001, 140 genetic loci have been found in whites using high-throughput genome-wide association studies. Several genes influence the CD subphenotypes and treatment response. With the observations of increasing prevalence in Asia and developing countries and the incomplete explanation of CD variance, other underexplored areas need to be integrated through novel methodologies. Algorithms that incorporate specific genetic risk alleles with other biomarkers will be developed and used to predict CD disease course, complications, and response to specific therapies, allowing precision medicine to become real in CD.

Introduction Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes. Methods This retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models. Results Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P < 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy. Discussion This study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.

A man in his sixth decade with Crohn's colitis and who had been taking infliximab for 18 months presented with fever and weight loss. Chest CT showed numerous nodules in both lungs, and sputum culture grew Mycobacterium tuberculosis. Colonoscopy showed circumferential ulcerations from the cecum to the descending colon, and biopsies showed extensive granulomas with central necrosis, positive for acid-fast bacteria. Brain MRI revealed a thalamic ring-enhanced mass with edema, consistent with tuberculoma. Clinicians should be aware of the appropriate screening and close monitoring of tuberculosis before and during anti-tumor necrosis factor (TNF) therapy.

Inflammatory bowel disease (IBD) has long been known to have genetic risk factors because of increased prevalence in the relatives of affected individuals. However, genome-wide association studies have only explained limited heritability in IBD. The observed globally rising incidence of IBD has implicated the role of environmental factors. The hidden unexplained heritability remains to be explored.Recent aggregate evidence has highlighted the extent and nature of host genome-microbiome associations, a key next step in understanding the mechanisms of pathogenesis in IBD. An individual's gut microbiota is shaped not only by genetic but also by environmental factors like diet. Minimizing exposure of the intestinal lumen to selected food items has shown to prolong the remission state of IBD. Among a genetically susceptible host, the shift of gut microbiota (or 'dysbiosis') can lead to increasing the susceptibility to IBD. With the advances in high-throughput large-scale 'omics' technologies in combination with creative data mining and system biology-based network analyses, the complexity of biological functional networks behind the cause of IBD has become more approachable. Therefore, the hidden heritability in IBD has become more explainable, and can be attributable to the changing environmental factors, epigenetic modifications, and gene-host microbial ('in-vironmental') or gene-extrinsic environmental interactions.This review discusses the perspectives of relevance to clinical translation with emphasis on gene-environment interactions. No doubt, the use of system-based approaches will lead to the development of alternative, and hopefully better, diagnostic, prognostic, and monitoring tools in the management of IBD.

Since the discovery of the first Crohn's disease (CD) gene NOD2 in 2001, 140 genetic loci have been found in whites using high-throughput genome-wide association studies. Several genes influence the CD subphenotypes and treatment response. With the observations of increasing prevalence in Asia and developing countries and the incomplete explanation of CD variance, other underexplored areas need to be integrated through novel methodologies. Algorithms that incorporate specific genetic risk alleles with other biomarkers will be developed and used to predict CD disease course, complications, and response to specific therapies, allowing precision medicine to become real in CD.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763

Background & Aims The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. Methods We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P −8 in meta-analysis with a nominal evidence ( P Results We detected SNPs at HLA-DRB1 , and African-specific SNPs at ZNF649 and LSAMP , with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication ( P −6 ): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B, PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2 ) for CD; and KCNQ2 (near TNFRSF6B ) for UC. Several of these genes, such as TNC (near TNFSF15 ), CXCR6 , and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. Conclusions We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

African Americans (AAs) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD.Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. Overall, 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 single nucleotide polymorphisms (SNPs) in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry.Mean EA was similar among the CD cases and controls (20.9% and 20.4%, respectively, P = 0.58). No significant admixture differences were observed among 211 to 227 cases stratified by phenotypic subclassifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, P = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, P = 0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (Leu503Phe [10.5% CD, 7.6% Controls, P = 0.05] and g-207c [41.3% CD, 35.7% Controls, P = 0.03], respectively), and IL23R rs2201841 (18.2% CD, 13.8% Controls, P = 0.03), but not IRGM variants, nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (P = 0.05), whereas a more common haplotype isolating g-207c was not.Specific functional gene variations contribute significantly to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls.

Background: To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer. Methods: We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI). Results: The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00–3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48–0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence. Conclusion: Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors. Impact: This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis. Cancer Epidemiol Biomarkers Prev; 21(10); 1774–82. ©2012 AACR.

Serum antibodies to Epstein–Barr virus (EBV) antigens can be used to predict the risk of nasopharyngeal carcinoma (NPC). To investigate whether EBV seropositivity rates were higher among healthy family members from multiplex and sporadic families with NPC (i.e., families with multiple or single cases) compared to the general population, a study was conducted on 2,665 unaffected individuals from 140 multiplex and 413 sporadic families. The titers of the IgA antibody to the EBV capsid antigen (VCA-IgA) were compared to those of 904 controls from the general population. The VCA-IgA titer was correlated among sibling pairs to a high significance in both family types (P

In this paper, we proposed a novel photo sensing pixel circuit for a large-area flexible e-reader utilizing an active matrix electrophoretic display (AMEPD). The photo sensing pixel consists of only 2 amorphous Si:H (a-Si:H) transistors to achieve light sensing, pixel switching and signal amplification functions without extra driving signals. The pixel output signal is up to 2V under illuminations of a common LED laser pointer. No degradation of the pixel output performance is observed after bending of more than 5000 times under 2cm curvature radius.

Optimization of medical therapy and specialist care for inflammatory bowel disease (IBD) may reduce morbidity. We sought to characterize racial disparities in utilization of healthcare and medical therapy for IBD.We performed a cross-sectional study of black (n=137) and white (n=149) IBD patients recruited from an outpatient IBD clinic and through medical record review and telephone interview, compared utilization of IBD specialist services, emergency department (ED) services, and medications. We adjusted racial comparisons for demographic, socioeconomic, and clinical factors.After adjustment for confounders, blacks were less likely than whites to be under the regular care (defined as at least annual visit) of a gastroenterologist (adjusted odds ratio (aOR) 0.43; 95% confidence interval (CI): 0.25-0.75) or IBD specialist (aOR 0.37; 95% CI: 0.22-0.61). Follow-up with a primary care provider was, however, similar between blacks and whites. Over the preceding 12 months, blacks were more likely than whites to have at least one visit to the ED (aOR 2.02; 95% CI: 1.22-3.35), but there was no difference in hospitalization. Among CD patients with prolonged steroid use, blacks were less likely than whites to have been on infliximab (aOR 0.41; 95% CI: 0.21-0.77), but there were no racial differences in the use of immunomodulators (aOR 0.87; 95% CI: 0.48-1.60).There are racial differences in utilization of IBD-related specialist services, ED visits, and infliximab that are independent of income and education. Modifiable barriers to health-care access may have a role in these disparities.

Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; p(combined) = 3.9 x 10(-20) and 1.6 x 10(-19), respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; p(combined) = 8.97 x 10(-17)) and HLA-F (rs3129055 and rs9258122; p(combined) = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p5 x 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.

Background: Incidence density sampling is typically the least biased efficient method for control sampling in nested case-control studies. However, in studies of genetic variants and prostate cancer progression, some argue that controls should be sampled from men who did not progress by end of follow-up. Thus, we examined the validity of relative risk (RR) estimates of prostate cancer progression using three methods for control sampling from cohorts of men with prostate cancer generated by Monte Carlo simulation. Methods: Data were simulated for nine scenarios for combinations of genotype frequency (10%, 30%, and 50%) and association (RR, 1.0, 1.5, and 2.0) using prostate progression rates from Johns Hopkins Hospital. RRs estimated from conditional logistic regression for the genetic association from case-control studies nested in the nine cohort scenarios using three control sampling methods, (a) incidence density sampling, (b) incidence density sampling without replacement of selected controls, and (c) “pure” control sampling (i.e., men who did not progress by end of long-term follow-up), were compared with the true RRs. Results: Use of controls selected by incidence density sampling produced unbiased RR estimates of progression. In our setting, only a slight bias was produced by use of incidence density sampling without replacement. In contrast, use of controls selected by pure control sampling produced biased RR estimates, except when there was no association; extent of bias increased with increasing size of the association and duration of follow-up. Conclusions: Nested case-control studies designed to estimate the association of genetic variants with risk of prostate cancer progression should use incidence density sampling to provide a valid RR estimate. (Cancer Epidemiol Biomarkers Prev 2009;18(3):706–11)

In a population-based case-control study we have previously shown that 14% of healthy Manitobans carry one or two mutations in the NOD-2 locus, a gene highly associated with Crohn's disease (CD). The NOD-2 protein is the receptor responsible for recognition of bacterial peptidoglycans, and it is plausible that NOD-2 is involved in the recognition of mycobacteria. Thirty-seven percent of Manitobans with CD had ≥1 NOD-2 mutation, leading to a threefold increased risk of CD for single-mutant carriers and a 30-fold increased risk for double-mutant carriers. In the same population groups, we assessed the seroprevalence forMycobacterium paratuberculosisand found it to be 35%, with no differences between CD, ulcerative colitis (UC), and controls. Because of high rates of CD and UC in Manitoba, we assessed whether there was an interaction between carrying a NOD-2 mutation andM. paratuberculosisseropositivity. An enzyme-linked immunosorbent assay for serum antibodies toM. paratuberculosisin cattle was adapted for human use. DNA was purified from whole blood. Subjects were genotyped for three NOD-2 variants, G908R, Cins1007fs, and R702W. Multivariate logistic regression analysis showed that NOD-2 gene mutations significantly associated with CD, butM. paratuberculosisserology did not. Furthermore, there was no interaction between NOD-2 mutation status andM. paratuberculosisserology status. For those with the NOD-2 mutation, the likelihood of CD subjects having positiveM. paratuberculosisserology was similar to that of controls (odds ratio, 1.31; 95% confidence interval, 0.55-3.11). No interaction could be proven for UC or by combining CD and UC compared to controls. In conclusion, we could not find an interaction between the NOD-2 genotype andM. paratuberculosisserology in relationship to CD or UC.

Multiple established Crohn's disease (CD) and ulcerative colitis (UC) risk factors including family history, tobacco use, Jewish ethnicity, urban residency, and CARD15/NOD2 mutations have been evaluated singly and in hospital-based observational studies. The goal of this study was to assess the relative contributions of all these risk factors jointly in a nonreferral, population-based cohort derived from a population epidemiologic database.CD (N = 232) and UC (N = 121) subjects were ascertained from our population-based IBD Registry derived from Manitoba Health, the single provincial insurer. Healthy controls (HC) (N = 336) were recruited via a 10:1 mailing matched for age, sex, and postal code. Ethnicity, tobacco use, family history, residency, and CARD15/NOD2 genotype status were determined.In both univariate analyses and analyses adjusted for all risk factors, CD was influenced independently by CARD15/NOD2 heterozygote and homozygote/compound-heterozygote status (adjusted odds ratios [OR] 3.7 and 40.0, respectively), Jewish ethnicity (OR 18.5), CD family history (OR 6.2), and smoking (OR 3.0 current and 1.7 ex-smoker, respectively). Penetrance for homozygote/compound-heterozygotes was 4.9%, heterozygotes 0.54%, and wild types 0.184%. Population attributable risk for CARD15 was 26.7% and current tobacco use was 46.8%. A tobacco-CARD15 interaction was not observed. UC was influenced by Jewish ethnicity (OR 37.1), and by family history (OR 2.6), ex-smoker status (OR 1.9), and CARD15/NOD2 heterozygote or homozygote/compound-heterozygote status (OR 1.9 and 6.4, respectively) in adjusted analyses only.CARD15/NOD2, family history, smoking, and Jewish ethnicity are independent risk factors for CD. Examination of these risk factors together in a single population-based cohort has provided initial data for population epidemiological characterization and genetic counseling uses.

1 A 63-year-old woman presented with drowsy consciousness and dyspnea, followed by respiratory failure, after taking a bottle of parathion for suicide. 2 Sinus tachycardia was noted initially by ECG and Q-T interval prolongation with pleomorphic ventricular tachyarrhythmia (`Torsade de pointes') occurred on the third day of admission. 3 Torsade de pointes was relieved by magnesium sulfate and atropine sulfate intravenously. Q-T interval returned to normal on the fifth day of admission. 4 Practicing physicians should be aware of this uncommon type of cardiac toxicity caused by organophosphate poisoning, Q-T interval prolongation and pleomorphic ventricular tachyarrhythmia.

The era of biologic therapy for inflammatory bowel disease was launched in 1998 with the Food and Drug Administration’s approval of infliximab (IFX), a chimeric monoclonal antibody to tumor necrosis factor-alpha (TNF-α), for Crohn’s disease (CD). However, it was not until 2005, after the results of several open-label clinical studies and of the ACT1 and ACT2 trials of IFX for treatment of moderate to severe ulcerative colitis (UC), that this agent was approved for therapy of UC. In a recent meta-analysis, it was estimated that the number of patients with UC needed to treat with IFX to achieve one remission was only four. However, as experience with using anti-TNF-α agents in CD has shown, the development of loss of response or intolerance to an initial anti-TNF-α agent, partly due to immunogenic effects, is a real problem and having other choices for blocking TNF-α is advantageous. Since 2012, the FDA has approved two other anti-TNF-α antibodies, adalimumab and golimumab, for the treatment of UC. In this chapter, we will review the evidence supporting the use of these agents for UC therapy.

BACKGROUND Genome-wide association studies have identified at least 71 Crohn's disease (CD) genetic risk loci, but the role of gene-gene interactions is unclear. The value of genetic variants in clinical practice is not defined because of limited explained heritability. METHODS We examined model predictability of combining the 71 CD risk alleles and genetic interactions in an ongoing inflammatory bowel disease genome-wide association study. The Wellcome Trust Case Control Consortium inflammatory bowel disease genome-wide association study was used as a replicate cohort. We used logic regression, an adaptive regression methodology, to search for high-order binary predictors (e.g., single-nucleotide polymorphism [SNP] interactions). RESULTS The combined 71 CD SNPs had good CD risk predictability (area under the curve of 0.75 and 0.73 in the 2 cohorts). Higher cumulative allele score predicted higher CD risk, but a relatively small difference in cumulative allele scores was observed between CD and controls (49 versus 47, P < 0.001). Through LR, we identified high-order genetic interactions and significantly improved the model predictability (area under the curve, from 0.75 to 0.77, P < 0.0001). A genetic interaction model, including NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci, was discovered and successfully replicated in the independent Wellcome Trust Case Control Consortium cohort. The explained heritability of the 71 CD SNPs alone was 24% and increased to 27% after adding the genetic interactions. CONCLUSIONS A novel approach allowed the identification and replication of genetic interactions among NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci. CD risk can be predicted by a model of 71 CD loci and improved by adding genetic interactions.