Lactase Non-persistence and Lactose Intolerance.

PURPOSE OF REVIEW: To evaluate the clinical and nutritional significance of genetically determined lactase non-persistence and potential lactose and milk intolerance in 65-70% of the world's adult population. RECENT FINDINGS: Milk consumption is decreasing in the USA and is the lowest in countries with a high prevalence of lactase non-persistence. The dairy industry and Minnesota investigators have made efforts to minimize the influence of lactose intolerance on milk consumption. Some lactose intolerant individuals, without co-existent irritable bowel syndrome, are able to consume a glass of milk with a meal with no or minor symptoms. The high frequency of lactase persistence in offspring of Northern European countries and in some nomadic African tribes is due to mutations in the promoter of the lactase gene in association with survival advantage of milk drinking. Educational and commercial efforts to improve calcium and Vitamin D intake have focused on urging consumption of tolerable amounts of milk with a meal, use of lowered lactose-content foods including hard cheeses, yogurt, and lactose-hydrolyzed milk products.

Association between serrated epithelial changes and colorectal dysplasia in inflammatory bowel disease.

BACKGROUND AND AIMS: Serrated epithelial change (SEC) is a histologic finding in longstanding colitis that may be associated with dysplasia. Our primary aim was to determine the incidence of dysplasia and colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients with SEC. Secondary aims were to determine the rate of location concordance between SEC and dysplasia/CRC and to identify other risk factors associated with dysplasia in IBD patients with SEC. METHODS: A retrospective, descriptive, observational study was performed by searching the Pathology Data System at a single tertiary referral center for a histologic finding of "serrated epithelial change." The patient's first pathology specimen with SEC was designated the index SEC. All subsequent pathology reports were evaluated for the occurrence and location of dysplasia or CRC. Univariable and multivariable logistic regression were performed to identify predictors of dysplasia. RESULTS: There were 187 patients with confirmed IBD and 1 or more histologic findings of SEC without prior dysplasia. Mean IBD duration was 16 years, and median follow-up time was 28 months. The rate of high-grade dysplasia or CRC was 17 per 1000 patient-years. Thirty-nine of 187 patients (21%) had synchronous or metachronous dysplasia or CRC. Location concordance was 68%. Multivariable analysis found SEC on follow-up examinations, older age at IBD diagnosis, male gender, and a first-degree relative with CRC were associated with dysplasia in IBD patients with SEC. CONCLUSIONS: This uncontrolled study describes a high frequency of dysplasia in patients with a histologic finding of SEC. SEC seen on successive endoscopic examinations further increased the risk of dysplasia. Further controlled studies are needed to determine if SEC is a precancerous lesion in IBD patients and if SEC can be endoscopically identified.

Infections Requiring Hospitalization as Predictors of Pediatric-Onset Crohn's Disease and Ulcerative Colitis.

Objectives. To assess the relationship between infections and the risk of pediatric-onset inflammatory bowel disease (IBD). Methods. We conducted a nested case-control study of 501 incident cases aged ≤17 years and 9,442 controls who were members of Kaiser Permanente Northern California for at least one consecutive year between 1996 and 2006. IBD was confirmed and the incidence date was adjudicated by pediatric gastroenterologists. Hospitalized infections were identified from the principal diagnosis code of electronic inpatient records. Medications to treat infections were identified during the hospitalization. Conditional logistic regression was used to assess the associations between hospitalized infections, medications, and Crohn's disease and ulcerative colitis. Results. In the year prior to diagnosis, both hospitalized infection of any system (OR 6.3; 95% CI 1.6-23.9) and hospitalized intestinal infection (OR 19.4; 95% CI 2.6-143.2) were associated with CD. Hospitalized infections of any system were inversely associated with UC after excluding the year prior to diagnosis (OR 0.4; 95% CI 0.2-0.9). No UC case had a hospitalized gastrointestinal infection prior to diagnosis. Conclusion. Infections appear to play opposite roles prior to the diagnosis of CD and UC. Infections may be associated with an increased risk of CD and a decreased risk of UC.

Family history of inflammatory bowel disease among patients with ulcerative colitis: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Despite numerous shared susceptibility loci between Crohn's disease and ulcerative colitis, the prevalence of family history among ulcerative colitis patients is not well-established and considered to be less prevalent. A systemic review and meta-analysis were conducted to estimate the prevalence of family history of inflammatory bowel disease in ulcerative colitis patients, and its effect on disease outcomes. METHODS: PubMED was searched to identify studies reporting the prevalence of family history of inflammatory bowel disease among ulcerative colitis patients. Definitions of family history, study type, and subtypes of family history prevalence were abstracted, as were disease outcomes including age at ulcerative colitis diagnosis, disease location, surgery and extraintestinal manifestations. Pooled prevalence estimates were calculated using random effects models. RESULTS: Seventy-one studies (86,824 patients) were included. The prevalence of a family history of inflammatory bowel disease in ulcerative colitis patients was 12% (95% confidence interval [CI] 11 to 13%; range 0-39%). Family history of ulcerative colitis (9%; 22 studies) was more prevalent than Crohn's disease (2%; 18 studies). Patients younger than 18years of age at time of diagnosis had a greater family history of inflammatory bowel disease (prevalence 15%, 95% CI: 11-20%; 13 studies). There were no differences in disease location, need for surgery, or extraintestinal manifestations among those with a family history, although very few studies reported on these outcomes. CONCLUSIONS: Overall, 12% of ulcerative colitis patients have a family history of inflammatory bowel disease, and were more likely to have a family history of ulcerative colitis than Crohn's disease. Pediatric-onset ulcerative colitis patients were more likely to have a family history of inflammatory bowel disease.

Editorial: Can stenosis in ileal Crohn's disease be prevented by current therapy?

Diagnostic delay is common with Crohn's disease (CD), especially with ileitis. Recent data show that diagnostic delay is associated with an increased risk of bowel stenosis and intestinal surgery. It is nonetheless unclear whether early diagnosis and treatment can truly prevent CD stenosis. Available cohort studies suggest that CD stricture formation occurs over a fixed time course. Current therapies have also not been shown to reduce the risk of ileal stenosis or rates of surgery, and there are no available therapies to reverse existing fibrosis. Development of medications that target fibrosis is an important area of research.

MicroRNA-224 negatively regulates p21 expression during late neoplastic progression in inflammatory bowel disease.

BACKGROUND: The development of colon cancer represents a major complication in patients with inflammatory bowel disease (IBD). The importance of microRNAs (miRs) in carcinogenesis is becoming clearer because miRs have been implicated in the regulation of cancer-related cellular processes to include apoptosis, differentiation, cell cycle progression, and immune function. In the current study, we sought to identify miR dysregulation specific to progression along the normal-inflammation-cancer axis in colonic specimens from patients with IBD. METHODS: MiR microarrays and quantitative reverse transcription PCR were used to detect and confirm dysregulated miRs. Receiver operating characteristic curve analysis was applied to evaluate the potential use of miR-224 as a neoplastic disease marker in IBD. For miR-224 target messenger RNA (mRNA) identification, mRNA microarrays were employed in combination with bioinformatic analyses, Western blotting, and luciferase activity measurements. RESULTS: We identified 30 miRs that were differentially expressed between chronically inflamed mucosae and cancers arising from IBD tissues. MiR-224 levels increased successively at each stage of IBD progression and accurately discriminated cancers from normal or chronically inflamed IBD tissues. Moreover, mRNA arrays combined with bioinformatic analyses suggested the participation of miR-224 in cell cycle regulation. Subsequently, cell cycle experiments indicated that miR-224 regulates the G1-S checkpoint. Finally, in silico prediction analyses, confirmed by Western blotting and luciferase assays, identified p21 as a specific direct mRNA target of miR-224. CONCLUSIONS: These findings reveal miR dysregulation specific to IBD-associated colorectal carcinoma. MiR-224 is overexpressed in IBD cancers and targets p21, a key cell cycle regulator. Moreover, these results establish the participation of miR-224 in IBD carcinogenesis.

Prenatal and perinatal characteristics associated with pediatric-onset inflammatory bowel disease.

BACKGROUND: The majority of studies that report early life risk factors for pediatric-onset inflammatory bowel disease (IBD) do not account for potential confounding, which can lead to spurious associations and incorrect inferences. AIMS: To assess the relationship between prenatal and perinatal characteristics and the risk of pediatric-onset IBD accounting for potential confounding. METHODS: We conducted a nested case-control study of 189 cases aged ≤18 years and 3,080 age- and membership-matched controls born at a Kaiser Permanente Northern California facility between 1984 and 2006. The cases were diagnosed with IBD between 1996 and 2006 and diagnosis was confirmed by chart review. We obtained prenatal and perinatal characteristics from the electronic clinical records of the mother and child. Conditional logistic regression was used to assess the associations between these factors and risk of incident IBD, Crohn's disease, and ulcerative colitis. RESULTS: In analyses accounting for confounding, maternal IBD (odds ratio [OR] 5.1, 95 % confidence interval [CI] 2.0-12.9) and white race (OR 2.3, 95 % CI 1.6-3.2) were the only factors statistically associated with pediatric-onset IBD. Maternal respiratory infection during pregnancy (OR 2.0, 95 % CI 1.0-4.0), age < 20 years (OR 2.0, 95 % CI 0.8-4.7) and gestational hypertension (OR 1.7, 95 % CI 1.0-2.7) were associated with pediatric-onset IBD, but did not achieve statistical significance. CONCLUSIONS: Maternal history of IBD and race were the only characteristics of those that we examined that were associated with the development of pediatric IBD in this well-documented population of cases and matched controls.

Serum anti-glycan antibody biomarkers for inflammatory bowel disease diagnosis and progression: a systematic review and meta-analysis.

BACKGROUND: Anti-glycan antibody serologic markers may serve as a useful adjunct in the diagnosis/prognosis of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). This meta-analysis/systemic review aimed to evaluate the diagnostic value, as well as the association of anti-glycan biomarkers with IBD susceptible gene variants, disease complications, and the need for surgery in IBD. METHODS: The diagnostic odds ratio (DOR), 95% confidence interval (CI), and sensitivity/specificity were used to compare the diagnostic value of individual and combinations of anti-glycan markers and their association with disease course (complication and/or need for surgery). RESULTS: Fourteen studies were included in the systemic review and nine in the meta-analysis. Individually, anti-Saccharomyces cervisiae antibodies (ASCA) had the highest DOR for differentiating IBD from healthy (DOR 21.1; 1.8-247.3; two studies), and CD from UC (DOR 10.2; CI 7.7-13.7; seven studies). For combination of ≥2 markers, the DOR was 2.8 (CI 2.2-3.6; two studies) for CD-related surgery, higher than any individual marker, while the DOR for differentiating CD from UC was 10.2 (CI 5.6-18.5; three studies) and for complication was 2.8 (CI 2.2-3.7; two studies), similar to individual markers. CONCLUSIONS: ASCA had the highest diagnostic value among individual anti-glycan markers. While anti-chitobioside carbohydrate antibody (ACCA) had the highest association with complications, ASCA and ACCA associated equally with the need for surgery. Although in most individual studies the combination of ≥2 markers had a better diagnostic value as well as higher association with complications and need for surgery, we found the combination performing slightly better than any individual marker in our meta-analysis.

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer. Aberrant microRNA (miR) expression has been linked to carcinogenesis; however, no reports document a relationship between IBD-related neoplasia (IBDN) and altered miR expression. In the current study we sought to identify specific miR dysregulation along the normal-inflammation-cancer axis. METHODS: miR microarrays and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) were used to detect dysregulated miRs. Receiver operating characteristic curve analysis was employed to test for potential usefulness of miR-31 as a disease marker of IBDNs. In silico prediction analysis, Western blot, and luciferase activity measurement were employed for target identification. RESULTS: Several dysregulated miRs were identified between chronically inflamed mucosae and dysplasia arising in IBD. MiR-31 expression increases in a stepwise fashion during progression from normal to IBD to IBDN and accurately discriminated IBDNs from normal or chronically inflamed tissues in IBD patients. Finally, we identified factor inhibiting hypoxia inducible factor 1 as a direct target of miR-31. CONCLUSIONS: Our study reveals specific miR dysregulation as chronic inflammation progresses to dysplasia. MiR-31 expression levels increase with disease progression and accurately discriminates between distinct pathological entities that coexist in IBD patients. The novel effect of miR-31 on regulating factor inhibiting hypoxia inducible factor 1 expression provides a new insight on the pathogenesis of IBDN.

Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn's disease.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) result from pathophysiologically distinct dysregulated immune responses, as evidenced by the preponderance of differing immune cell mediators and circulating cytokine expression profiles. MicroRNAs (miRNAs) are small, noncoding RNAs that act as negative regulators of gene expression and have an increasingly recognized role in immune regulation. We hypothesized that differences in circulating immune cells in CD and UC patients are reflected by altered miRNA expression and that miRNA expression patterns can distinguish CD and UC from normal healthy individuals. METHODS: Peripheral blood was obtained from patients with active CD, inactive CD, active UC, inactive UC, and normal healthy adults. Total RNA was isolated and miRNA expression assessed using miRNA microarray and validated by mature miRNA quantitative reverse-transcription polymerase chain reaction. RESULTS: Five miRNAs were significantly increased and two miRNAs (149* and miRplus-F1065) were significantly decreased in the blood of active CD patients as compared to healthy controls. Twelve miRNAs were significantly increased and miRNA-505* was significantly decreased in the blood of active UC patients as compared to healthy controls. Ten miRNAs were significantly increased and one miRNA was significantly decreased in the blood of active UC patients as compared to active CD patients. CONCLUSIONS: Peripheral blood miRNAs can be used to distinguish active CD and UC from healthy controls. The data support the evidence that CD and UC are associated with different circulating immune cells types and that the differential expression of peripheral blood miRNAs may form the basis of future diagnostic tests for inflammatory bowel disease.

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

Identification of microRNAs associated with ileal and colonic Crohn's disease.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are associated with expression differences in genes involved in immune function, wound healing, and tissue remodeling. MicroRNAs (miRNAs) are small, noncoding RNAs that act as potent negative regulators of gene expression and are differentially expressed in chronic inflammatory diseases, including UC. We examined the expression of miRNAs in tissues from different intestinal regions and in patients with active ileal and colonic CD. METHODS: Colonoscopic pinch biopsies were obtained from the terminal ileum, cecum, transverse colon, sigmoid colon, and rectum of normal, healthy adults and from the ileum and sigmoid colon of patients with active ileal and colonic CD. miRNA expression was assessed using miRNA microarray and validated by mature miRNA quantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: Ten intestine region-specific miRNAs were identified. Three miRNAs were increased and one miRNA was decreased in the terminal ileum as compared to the colon. Six other miRNAs expressed varying levels of expression among the colon regions. Five miRNAs were found to be differentially expressed in tissues of patients with active colonic CD, with three increased and two decreased as compared to normal, healthy controls. Similarly, four miRNAs were found to be significantly increased in tissues of patients with active ileal CD. CONCLUSIONS: The expression differences between ileal CD, colonic CD, and previously identified UC-associated miRNAs support the likelihood that miRNAs influence differing inflammation-related gene expression in each inflammatory bowel disease (IBD) subtype and may form the basis for future diagnostic tests and therapeutic targets for IBD.

NOD2 mutations and anti-Saccharomyces cerevisiae antibodies are risk factors for Crohn's disease in African Americans.

OBJECTIVES: NOD2 mutations and anti-Saccharomyces cerevisiae antibodies (ASCAs) are established risk factors of Crohn's disease (CD) in whites but have not been assessed in African-American (AA) adults with CD. METHODS: AAs with CD and controls were recruited by the Mid-Atlantic African-American IBD Study as part of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium. Genotyping for the three common CD NOD2 mutations (Leu1007fsinsC, G908R/2722g>c, and R702W/2104c>t) and ASCA enzyme-linked immunosorbent assays were performed in 183 AA CD patients and in 143 controls. Logistic regression was used to calculate adjusted odds ratios (ORs) for the association between ASCA and disease phenotype. RESULTS: ASCA sensitivity and specificity values were 70.5 and 70.4%, respectively. On univariate analysis, ASCA was significantly associated with younger age at diagnosis, ileal involvement, and complicated (stricturing/penetrating) behavior. On multivariate analysis, ASCA titer (per 25 Units) was associated with ileal involvement (OR 1.18, 95% confidence interval (CI): 1.04-1.34), complicated behavior (OR 1.13, 95% CI: 1.01-1.28), and surgery (hazard ratio: 1.11, 95% CI: 1.02-1.21). Cigarette smoking and CD family history were also significantly associated with surgery. NOD2 carriers (all heterozygotes) were more common among CD cases than controls (8.2 vs. 2.1%; OR 4.17%, 95% CI: 1.18-14.69). The NOD2 mutation population attributable risk was 6.2%. CONCLUSIONS: In comparison with whites, ASCA in AAs has a similar sensitivity but a lower specificity for CD. ASCA is associated with ileal involvement, complicated behavior, and surgery in AAs with CD. NOD2 is a risk gene for AA CD, although mutation frequency and population attributable risk are much lower than in whites.

Refractory lymphocytic enterocolitis and tumor necrosis factor antagonist therapy.

BACKGROUND & AIMS: Lymphocytic enterocolitis is a malabsorptive syndrome characterized by severe small-bowel villous abnormality and crypt hyperplasia and dense infiltrate of lymphocytes throughout the gastrointestinal tract. METHODS: We present 2 patients with lymphocytic enterocolitis refractory to usual medical therapy who were treated with tumor necrosis factor antagonists. RESULTS: Both patients had clinical improvement in diarrheal symptoms and intestinal histologic abnormalities. CONCLUSIONS: Tumor necrosis factor-alpha antagonists such as infliximab or adalimumab may be a new treatment option for patients with severe refractory lymphocytic enterocolitis not responding to corticosteroids.

Prediction of the need for surgical intervention in obstructive Crohn's disease by 18F-FDG PET/CT.

UNLABELLED: We preoperatively determined the accuracy of (18)F-FDG PET/CT for differentiating fixed muscle hypertrophy and fibrotic stenoses from acute transmural inflammatory stenoses in patients with Crohn's disease (CD) scheduled to undergo surgical resection for obstructive symptoms. METHODS: Seventeen patients with known CD prospectively underwent (18)F-FDG PET/CT before already-planned surgery for obstructive symptoms. Image interpretation was by consensus of 2 readers with knowledge of patient participation in the study but not of other clinical history. Lesions were qualitatively graded on a 5-point scale for the presence of increased (18)F-FDG uptake consistent with active inflammation. Maximum lean standardized uptake value (SUL(max)) was determined for lesions scored 1 or more. Imaging results were compared with the pathologic grading of inflammation and predominant histopathologic subtype for each patient's surgical specimen, whether mainly inflammation, fibrosis, or muscle hypertrophy. RESULTS: Thirteen of the 17 patients underwent surgery (median, 28 d after PET/CT; range, 2-148 d), and 12 of these 13 had histopathologic correlation. Despite the predominant histopathologic subtype (inflammation, 5; fibrosis, 4; and muscle hypertrophy, 3), acute and chronic inflammation, fibrosis (median, 50%; range, 40%-90%), and muscle hypertrophy (median, 20-fold thickening; range, 9- to 40-fold thickening) were found in all patients. SUL(max) was significantly higher in severe than in mild-to-moderate chronic inflammation (8.2 +/- 2.8 vs. 4.7 +/- 2.5, P = 0.04). No patient with predominantly fibrosis or muscle hypertrophy (n = 7) had an SUL(max) greater than 8. Visually, 10 of 12 patients on PET/CT were considered to have active inflammation of the bowel. CONCLUSION: Patients with CD who undergo surgery for obstructive symptoms have histopathologically mixed findings of inflammation, fibrosis, and muscle hypertrophy. Qualitative PET interpretations were quite sensitive, but additional semiquantitative analyses using SUL(max) helped identify patients with active inflammation. This information may be beneficial for referring gastroenterologists considering medical therapy versus surgery for patients with CD who present with obstructive symptoms.

Identification of novel serological biomarkers for inflammatory bowel disease using Escherichia coli proteome chip.

Specific antimicrobial antibodies present in the sera of patients with inflammatory bowel disease (IBD) have been proven to be valuable serological biomarkers for diagnosis/prognosis of the disease. Herein we describe the use of a whole Escherichia coli proteome microarray as a novel high throughput proteomics approach to screen and identify new serological biomarkers for IBD. Each protein array, which contains 4,256 E. coli K12 proteins, was screened using individual serum from healthy controls (n = 39) and clinically well characterized patients with IBD (66 Crohn disease (CD) and 29 ulcerative colitis (UC)). Proteins that could be recognized by serum antibodies were visualized and quantified using Cy3-labeled goat anti-human antibodies. Surprisingly significance analysis of microarrays identified a total of 417 E. coli proteins that were differentially recognized by serum antibodies between healthy controls and CD or UC. Among those, 169 proteins were identified as highly immunogenic in healthy controls, 186 proteins were identified as highly immunogenic in CD, and only 19 were identified as highly immunogenic in UC. Using a supervised learning algorithm (k-top scoring pairs), we identified two sets of serum antibodies that were novel biomarkers for specifically distinguishing CD from healthy controls (accuracy, 86 +/- 4%; p < 0.01) and CD from UC (accuracy, 80 +/- 2%; p < 0.01), respectively. The Set 1 antibodies recognized three pairs of E. coli proteins: Era versus YbaN, YhgN versus FocA, and GabT versus YcdG, and the Set 2 antibodies recognized YidX versus FrvX. The specificity and sensitivity of Set 1 antibodies were 81 +/- 5 and 89 +/- 3%, respectively, whereas those of Set 2 antibodies were 84 +/- 1 and 70 +/- 6%, respectively. Serum antibodies identified for distinguishing healthy controls versus UC were only marginal because their accuracy, specificity, and sensitivity were 66 +/- 5, 69 +/- 5, and 61 +/- 7%, respectively (p < 0.04). Taken together, we identified novel sets of serological biomarkers for diagnosis of CD versus healthy control and CD versus UC.

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Patient trust-in-physician and race are predictors of adherence to medical management in inflammatory bowel disease.

BACKGROUND: Adherence plays an important role in the therapeutic effectiveness of medical therapy in inflammatory bowel disease (IBD). We assessed whether trust-in-physician and Black race were predictors of adherence. METHODS: We performed a cross-sectional study of Black (n = 120) and White (n = 115) IBD patients recruited from an outpatient IBD clinic. Self-reported adherence to taking medication and keeping appointments, trust-in-physician, and health-related quality of life were measured using the validated instruments, the modified Hill-Bone Compliance Scale (HBCS), the Trust-in-Physician Scale (TIPS), and the Short IBD Questionnaire (SIBDQ), respectively. RESULTS: Overall adherence was 65%. Higher adherence correlated with greater trust-in-physician (r = -0.30; P < 0.0001), increasing age (r = -0.19; P = 0.01), and worsening health-related quality of life (r = -0.18; P = 0.01). Adherence was also higher among White IBD patients compared to Blacks (HBSC: 15.6 versus 14.0, P < 0.0001). Trust-in-physician, race, and age remained predictors of adherence to medical management after adjustment for employment, income, health insurance, marital and socioeconomic status, and immunomodulator therapy. The adjusted odds ratio for adherence in Blacks compared to Whites was 0.29 (95% confidence interval: 0.13-0.64). Every half standard deviation increase in trust-in-physician and every incremental decade in age were associated with 36% and 47% higher likelihood of adherence, respectively. CONCLUSIONS: Trust-in-physician is a potentially modifiable predictor of adherence to IBD medical therapy. Black IBD patients exhibited lower adherence compared to their White counterparts. Understanding the mechanisms of these racial differences may lead to better optimization of therapeutic effectiveness.

MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha.

BACKGROUND & AIMS: Chronic inflammatory bowel diseases such as ulcerative colitis (UC) are associated with differential expression of genes involved in inflammation and tissue remodeling. MicroRNAs (miRNAs), which direct mRNA degradation and translational inhibition, influence a number of disease processes. We examined whether miRNAs are differentially expressed in UC tissues and are associated with expression of genes that regulate inflammation. METHODS: miRNA expression was assessed in patients with active UC, inactive UC, Crohn's disease, irritable bowel syndrome, infectious colitis, and microscopic colitis, as well as in healthy subjects by microarray, quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses. Colonic epithelial cell (HT29) expression of miRNAs was assessed. Regulation of gene expression by miRNAs was assessed by luciferase reporter construct assays and transfection of specific miRNA mimics. RESULTS: Active UC was associated with the differential expression of 11 miRNAs; 3 were significantly decreased and 8 were significantly increased in UC tissues. In situ hybridization analysis indicated that miR-192, an miRNA with decreased expression in active UC, was predominantly localized to colonic epithelial cells. Macrophage inflammatory peptide (MIP)-2 alpha, a chemokine expressed by epithelial cells, was identified as a target of miR-192. In colon epithelial cells, induction of MIP-2 alpha expression by tumor necrosis factor-alpha was accompanied by a concomitant reduction in miR-192 expression and miR-192 was observed to regulate the expression of MIP-2 alpha. CONCLUSIONS: These findings expand the known roles of miRNAs, indicating that tissues from patients with UC, and possibly other chronic inflammatory diseases, have altered miRNA expression patterns. These findings also demonstrate that miRNAs regulate colonic epithelial cell-derived chemokine expression.