A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.

Diagnostic reasoning in internal medicine: a practical reappraisal.

The practice of clinical medicine needs to be a very flexible discipline which can adapt promptly to continuously changing surrounding events. Despite the huge advances and progress made in recent decades, clinical reasoning to achieve an accurate diagnosis still seems to be the most appropriate and distinctive feature of clinical medicine. This is particularly evident in internal medicine where diagnostic boundaries are often blurred. Making a diagnosis is a multi-stage process which requires proper data collection, the formulation of an illness script and testing of the diagnostic hypothesis. To make sense of a number of variables, physicians may follow an analytical or an intuitive approach to clinical reasoning, depending on their personal experience and level of professionalism. Intuitive thinking is more typical of experienced physicians, but is not devoid of shortcomings. Particularly, the high risk of biases must be counteracted by de-biasing techniques, which require constant critical thinking. In this review, we discuss critically the current knowledge regarding diagnostic reasoning from an internal medicine perspective.

Recent advances in coeliac disease.

PURPOSE OF REVIEW: Worldwide awareness of coeliac disease in all ages continues to grow. This article aims to summarize critically the recent research advances in coeliac disease. RECENT FINDINGS: Large multicentre studies have provided further evidence of the role of environmental and nonhuman leucocyte antigen genetic factors in coeliac disease. Siblings of coeliac patients carry a high risk, but those found to have negative coeliac serology are very unlikely to develop the disease. Advances in the efficacy of serological antibody testing potentiate the possibility of future accurate screening programmes in the community. Adherence to a gluten-free diet remains paramount as the recognition of coeliac related complications increases. SUMMARY: Despite the encouraging progress that has taken place in our genetic and immunological knowledge of coeliac disease, early introduction of a gluten-free diet remains the cornerstone of treatment. Alternatives, however, aimed at altering the toxicity of cereal proteins are now looking more promising.

Advances in coeliac disease.

PURPOSE OF REVIEW: The number of people diagnosed with coeliac disease continues to rise, and this article critically summarizes recent research into the condition. RECENT FINDINGS: Much work has been focused on clarifying the molecular pathways involving cytokines in coeliac disease. Such work will yield improved understanding of the complex pathogenesis of coeliac disease and novel therapeutic targets. SUMMARY: The recent literature predominantly focuses on both elucidating the pathogenesis and improving diagnostic strategies for coeliac disease, but further work into the treatment of coeliac disease is needed.

Evidence for the involvement of NOD2 in regulating colonic epithelial cell growth and survival.

AIM: To investigate the function of NOD2 in colonic epithelial cells (CEC). METHODS: A combination of in vivo and in vitro analyses of epithelial cell turnover in the presence and absence of a functional NOD2 protein and, in response to enteric Salmonella typhimurium infection, were used. shRNA interference was also used to investigate the consequences of knocking down NOD2 gene expression on the growth and survival of colorectal carcinoma cell lines. RESULTS: In the colonic mucosa the highest levels of NOD2 expression were in proliferating crypt epithelial cells. Muramyl dipeptide (MDP), that is recognized by NOD2, promoted CEC growth in vitro. By contrast, the growth of NOD2-deficient CECs was impaired. In vivo CEC proliferation was also reduced and apoptosis increased in Nod2(-/-) mice, which were also evident following enteric Salmonella infection. Furthermore, neutralization of NOD2 mRNA expression in human colonic carcinoma cells by shRNA interference resulted in decreased survival due to increased levels of apoptosis. CONCLUSION: These findings are consistent with the involvement of NOD2 protein in promoting CEC growth and survival. Defects in proliferation by CECs in cases of CD may contribute to the underlying pathology of disrupted intestinal homeostasis and excessive inflammation.

Gliadin, glutenin or both? The search for the Holy Grail in coeliac disease.

Wheat gluten was traditionally classified into gliadin and glutenin based upon solubility in aqueous alcohol. Gliadins were thought to be responsible for precipitating coeliac disease; glutenins were thought probably to be nontoxic. More recent classification, according to primary amino acid structure, reveals not only great heterogeneity but also similarities between different gliadin and glutenin proteins. Peptides derived from both groups are immunostimulatory in coeliac disease and it is highly probable that glutenin proteins are therefore toxic. Attempts to breed wheat with satisfactory baking properties tolerated by coeliac patients will be very difficult.

Celiac disease.

Celiac disease is more prevalent than it was previously thought to be, and screening of selected population groups may reveal many new cases. Tissue transglutaminase appears to have a significant role in the degradation of gliadin and antigen production. Specific gliadin epitopes have been defined using T-cell responses. Bone disease is a significant problem for patients with celiac disease but management guidelines are being developed. Refractory sprue (nonresponsive celiac disease) appears to be a manifestation of enteropathy-associated T-cell lymphoma in most cases.

High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas.

PURPOSE: The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment. EXPERIMENTAL DESIGN: Forty-eight small bowel adenocarcinomas (33 non-celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease-related and non-celiac disease-related small bowel adenocarcinomas. RESULTS: DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease-related and non-celiac disease-related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non-celiac disease-related and 73% celiac disease-related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non-celiac disease-related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease-related small bowel adenocarcinomas were microsatellite unstable. CONCLUSIONS: Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease-related and non-celiac disease-related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease-related than in non-celiac disease-related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease-related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391-401.

Joint BAPEN and British Society of Gastroenterology Symposium on 'Coeliac disease: basics and controversies'. Dietitians are better than clinicians in following up coeliac disease.

It seems obvious to healthcare professionals that patients with coeliac disease should receive regular follow-up. Surprisingly, there is little evidence that patients benefit in terms of reduced morbidity or mortality. However, several authoritative bodies have published guidelines on the management of coeliac disease that recommend regular follow-up. There is good evidence that compliance with a gluten-free diet reduces the risk of complications such as osteoporosis or small bowel lymphoma. Compliance is enhanced particularly by education about the disease and the gluten-free diet and by support from peers or professionals. Such input can be provided by regular follow-up, which thereby should improve compliance and hence long-term health. The consensus of the recommendations for follow-up suggests an annual review by a physician and dietitian. At annual follow-up the disease status can be checked and nutritional advice can be given, including checking the adequacy of, and the compliance with, the gluten-free diet. Complications and associated medical conditions can be sought, genetic risks explained and support and reassurance given. Specialist dietitians have particular expertise in relation to diet and nutritional management; specialist clinicians have a broader range of expertise in many aspects of management of the disease. A team approach for providing follow-up is the ideal, with a clinician and dietitian, both with expertise in coeliac disease, being involved. No one particular group of healthcare professionals is necessarily better than the other at providing follow-up.

Newly identified genetic risk variants for celiac disease related to the immune response.

Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.