Deborah D. Proctor

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

We undertook a meta-analysis of six Crohns 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 Crohns disease.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia

Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

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 × 10−13, combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 × 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 × 10−16, combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 × 10−8, combined OR = 0.56; rs10889677, combined P = 1.3 × 10−8, combined OR = 1.29).

A genome-wide scan of ashkenazi jewish crohn's disease suggests novel susceptibility loci

Crohns disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10−6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10−8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10−9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10−8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10−8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10−9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

Spectrum of histologic changes in colonic biopsies in patients treated with mycophenolate mofetil

Mycophenolate mofetil, an immunosuppressive agent, is frequently used following bone marrow and solid organ transplantation. Diarrhea is a commonly seen side effect of mycophenolate mofetil, which may necessitate colonic biopsy in some patients. The histologic changes found in this setting have been reported to mimic self-limited colitis, graft-vs-host disease or inflammatory bowel disease in isolated case reports, and could pose diagnostic and management difficulties. The goal of this study is to define the spectrum of histologic changes in colonic biopsies associated with mycophenolate mofetil usage. All solid organ transplant patients who received mycophenolate mofetil and underwent colonic biopsy for gastrointestinal symptoms from 1999 to 2007 were included in the study. Patients who did not receive mycophenolate mofetil were used as controls. Various histologic features including architectural distortion, apoptosis, inflammatory infiltrate, Paneth cell metaplasia and mucin depletion were subjectively evaluated and scored (scale: 0–3) by two independent reviewers in a blinded fashion. Forty solid organ transplant patients underwent colonic biopsy for gastrointestinal symptoms during the study period. Biopsies from 69% of patients on mycophenolate mofetil showed histologic changes. Apoptosis (41%) and architectural distortion (66%) were seen more frequently in patients receiving mycophenolate mofetil as compared to the control group (13%). The histologic changes in patients receiving mycophenolate mofetil were categorized as normal/near normal (31%), inflammatory bowel disease-like (28%), graft-vs-host disease-like (19%), ischemia-like (3%) and self-limited colitis-like (16%) changes. Of the controls, only one patient showed a graft-vs-host disease-like histologic pattern. In conclusion, histologic changes are frequently associated with mycophenolate mofetil use and can resemble self-limited colitis, graft-vs-host disease and inflammatory bowel disease leading to diagnostic difficulties. Increased awareness of the histologic spectrum of mycophenolate mofetil-induced changes is required by the pathologist to avoid diagnostic errors.

Diagnosis and Management of Gastrointestinal Bleeding in Patients With Hereditary Hemorrhagic Telangiectasia

OBJECTIVE:Our aim was to report our experience with treating GI bleeding in patients with hereditary hemorrhagic telangiectasia (HHT).METHODS:Consecutive patients with GI bleeding referred to the Yale University Vascular Malformation Center underwent clinical evaluation and endoscopy. Hb and blood transfusion requirements for 1 yr before and after evaluation were documented. Patients with a mean Hb ≤ 8 mg/dl or blood transfusion requirements ≥ 12 units packed red blood cells (PRBC)/yr were defined as patients with significant bleeding. Drug therapies, including ethinyl estradiol/norethindrone, danazol, and aminocaproic acid, were prescribed on an individual patient basis.RESULTS:The study included 43 HHT patients with a mean age of 57 yr. Endoscopy revealed telangiectases in the esophagus (1/41), stomach (33/41), duodenum (33/41), jejunum (5/9), and colon (10/32). Patients with > 20 telangiectases visualized on esophagogastroduodenoscopy had a significantly lower mean Hb of 7.9, compared with 9.4 (P = 0.007), and a trend toward higher blood transfusion requirements. Non–HHT-related causes of GI bleeding were diagnosed in four patients. During a mean follow up of 18.9 months, the group of 40 patients with HHT-related bleeding had improvements in their mean Hb and blood transfusion requirements.CONCLUSIONS:Some HHT patients with GI bleeding improve on drug therapies, but others fail. Transfusion-dependent GI bleeding is difficult to manage, and optimal management may include both medical and endoscopic treatments.

Relationship between proximal Crohn's disease location and disease behavior and surgery: a cross-sectional study of the IBD Genetics Consortium.

OBJECTIVES:In classifying Crohns disease (CD) location, proximal (L4) disease includes esophagogastroduodenal (EGD) and jejunal disease. Our aim was to determine the influence of proximal disease on outcomes of behavior and need for surgery and to determine if there was significant clinical heterogeneity between EGD and jejunal disease.METHODS:We performed a cross-sectional query of the NIDDK (National Institute of Diabetes and Digestive and Kidney Disease) Inflammatory Bowel Disease Genetics Consortium (IBDGC) database of patients with a confirmed diagnosis of CD and phenotyped per the IBDGC manual. Presence of any L4, L4-EGD, L4-jejunal, and non-L4 disease (L1-ileal, L2-colonic, and L3-ileocolonic) was compared with demographic features including age, race, ethnicity, smoking and inflammatory bowel disease (IBD) family history, diagnosis age, disease duration, clinical outcomes of inflammatory, stricturing or penetrating behavior, and CD abdominal surgeries. Univariate and multivariable analyses were performed with R.RESULTS:Among 2,105 patients with complete disease location data, 346 had L4 disease (175 L4-EGD, 115 L4-jejunal, and 56 EGD and jejunal) with 321 having concurrent L1-L3 disease. In all, 1,759 had only L1-L3 disease. L4 vs. non-L4 patients were more likely (P<0.001) to be younger at diagnosis, non-smokers, have coexisting ileal involvement, and have stricturing disease. L4-jejunal vs. L4-EGD patients were at least twice as likely (P<0.001) to have had ileal disease, stricturing behavior, and any or multiple abdominal surgeries. Remarkably, L4-jejunal patients had more (P<0.001) stricturing behavior and multiple abdominal surgeries than non-L4 ileal disease patients. Logistic regression showed stricturing risks were ileal (without proximal) site (odds ratio (OR) 3.18; 95% confidence interval 2.23–4.64), longer disease duration (OR 1.33/decade; 1.19–1.49), jejunal site (OR 2.90; 1.89–4.45), and older age at diagnosis (OR 1.21/decade; 1.10–1.34). Multiple surgery risks were disease duration (OR 3.74/decade; 3.05–4.64), penetrating disease (OR 2.60; 1.64–4.21), and jejunal site (OR 2.39; 1.36–4.20), with short duration from diagnosis to first surgery protective (OR 0.87/decade to first surgery; 0.84–0.90).CONCLUSIONS:Jejunal disease is a significantly greater risk factor for stricturing disease and multiple abdominal surgeries than either EGD or ileal (without proximal) disease. The Montreal site classification should be revised to include separate designations for jejunal and EGD disease.

Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial.

Proton pump inhibitors (PPIs) are the most potent gastric acid suppressing drugs available, and their use is widespread. An emerging concern about chronic PPI therapy is whether these drugs impair intestinal calcium absorption, resulting in a negative calcium balance and thereby potentially causing bone loss. The objective of this study was to evaluate the acute effect of the PPI esomeprazole or placebo on intestinal calcium absorption in healthy adults. Twelve young adults participated in a placebo‐controlled, double‐blind, crossover study. There were two 3‐week interventions that included a 14‐day adjustment period (designed to stabilize calcium homeostasis) followed by 6 days of a diet containing 800 mg of calcium and 2.1 g/kg of protein (intervention). During the last 3 days of the adjustment period and throughout the intervention period, subjects consumed esomeprazole or placebo. Half the subjects underwent 24‐hour continuous gastric acid pH monitoring. Intestinal calcium absorption was measured using dual‐stable calcium isotopes at the end of each intervention. Treatment with esomprazole significantly increased gastric pH (mean pH on PPI 5.38 ± 0.13, mean pH on placebo 2.70 ± 0.44, p = .005). Neither calcium absorption (PPI 34.2% ± 2.4%, placebo 31.5% ± 2.1%, p = .24) nor urinary calcium (PPI 321 ± 38 mg/34 hours, placebo 355 ± 37 mg/34 hours, p = .07) differed between the PPI and placebo groups. It is concluded that short‐term gastric acid suppression by PPIs does not attenuate intestinal calcium absorption in healthy young adults.

EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) Study Identifies Fecal Calprotectin, Serum MMP9, and Serum IL-22 as a Novel Combination of Biomarkers for Crohn's Disease Activity: Role of Cross-Sectional Imaging

Objectives:In Crohns disease (CD), clinical symptoms correspond poorly to inflammatory disease activity. Biomarkers reflective of mucosal and bowel wall inflammation would be useful to monitor disease activity. The EMBARK study evaluated disease activity in patients with ulcerative colitis (UC) and CD, and used endoscopy with or without cross-sectional imaging for biomarker discovery.Methods:UC (n=107) and CD (n=157) patients were characterized and underwent ileocolonoscopy (ICO). A subset of CD patients (n=66) also underwent computed tomography enterography (CTE). ICO and CTE were scored by a gastroenterologist and radiologist who incorporated findings of inflammation into a single score (ICO-CTE) for patients that underwent both procedures. Serum and fecal biomarkers were evaluated for association with the Mayo Clinic endoscopy score in UC patients and with ICO alone or ICO-CTE in CD patients. Individual biomarkers with a moderate degree of correlation (P≤0.3) were evaluated using multivariate analysis with model selection using a stepwise procedure.Results:In UC, ordinal logistic regression using Mayo Clinic endoscopy subscore selected the combination of fecal calprotectin and serum matrix metalloproteinase 9 (MMP9; pseudo R2=0.353). In CD, we found that use of the ICO-CTE increased specificity of known biomarkers. Using ICO-CTE as the dependent variable for biomarker discovery, the selected biomarkers were the combination of fecal calprotectin, serum MMP9, and serum IL-22 (r=0.699).Conclusions:Incorporation of both ICO and CTE into a single measure increased biomarker performance in CD. Combinations of fecal calprotectin and serum MMP9 for UC, and combinations of fecal calprotectin, serum MMP9, and serum interleukin-22 in CD, demonstrated the strongest association with imaging/endoscopy-defined inflammation.

Proton pump-inhibiting drugs, calcium homeostasis, and bone health

Proton pump inhibitors (PPIs) are commonly used drugs, several of which are available without a prescription. Two recent studies have demonstrated increased hip fracture rates associated with PPI use. Theoretically, PPIs could impair intestinal calcium absorption resulting in increased rates of bone loss and a greater risk of fragility fracture.