Sjoerd F. Bakker

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.

Frequent delay of coeliac disease diagnosis in symptomatic patients with type 1 diabetes mellitus: Clinical and genetic characteristics

BACKGROUND Patients with type 1 diabetes mellitus (T1DM) are more prone to develop other auto-immune diseases, including coeliac disease (CD). Paediatric patients with T1DM are screened for CD, whereas in adult T1DM patients screening programs for CD are not standardised. The aim of this study was to investigate clinical and genetic characteristics of patients with both diagnoses so as to lead to better detection of CD in adult patients with T1DM. METHODS We studied 118 patients with both T1DM and CD identified in The Netherlands. We retrospectively collected data on sex distribution, age of onset of T1DM, age of CD diagnosis, CD complaints, duration of CD complaints before CD diagnosis, family history of CD or T1DM, comorbidity and HLA-DQ type. RESULTS Thirty-three percent of T1DM+CD patients reported CD related complaints for at least 5 years before CD diagnosis. Two peaks in the age of CD diagnosis in T1DM patients were observed: around 10 and 45 years of age. Women were diagnosed with CD at a younger age than men (median 25 years (IQR 9-38) versus 39 (12-55) years, respectively, P<0.05). CONCLUSION A delay of CD diagnosis is frequently found in adult T1DM patients and two peaks in the age of CD diagnosis are present in T1DM patients. This observational study emphasises that more frequent screening for CD in particularly adult T1DM patients is required, preferably by a 5 years interval.

Determinants of Gliadin-Specific T Cell Selection in Celiac Disease

In HLA-DQ8–associated celiac disease (CD), the pathogenic T cell response is directed toward an immunodominant α-gliadin–derived peptide (DQ8-glia-α1). However, our knowledge of TCR gene usage within the primary intestinal tissue of HLA-DQ8+ CD patients is limited. We identified two populations of HLA-DQ8-glia-α1 tetramer+ CD4+ T cells that were essentially undetectable in biopsy samples from patients on a gluten-free diet but expanded rapidly and specifically after antigenic stimulation. Distinguished by expression of TRBV9, both T cell populations displayed biased clonotypic repertoires and reacted similarly against HLA-DQ8-glia-α1. In particular, TRBV9 paired most often with TRAV26-2, whereas the majority of TRBV9− TCRs used TRBV6-1 with no clear TRAV gene preference. Strikingly, both tetramer+/TRBV9+ and tetramer+/TRBV9− T cells possessed a non–germline-encoded arginine residue in their CDR3α and CDR3β loops, respectively. Comparison of the crystal structures of three TRBV9+ TCRs and a TRBV9− TCR revealed that, as a result of distinct TCR docking modes, the HLA-DQ8-glia-α1 contacts mediated by the CDR3-encoded arginine were almost identical between TRBV9+ and TRBV9− TCRs. In all cases, this interaction centered on two hydrogen bonds with a specific serine residue in the bound peptide. Replacement of serine with alanine at this position abrogated TRBV9+ and TRBV9− clonal T cell proliferation in response to HLA-DQ8-glia-α1. Gluten-specific memory CD4+ T cells with structurally and functionally conserved TCRs therefore predominate in the disease-affected tissue of patients with HLA-DQ8–mediated CD.

Contrasting the Genetic Background of Type 1 Diabetes and Celiac Disease Autoimmunity

Type 1 diabetes (T1D) and celiac disease (CeD) cluster in families and can occur in the same individual. Genetic loci have been associated with susceptibility to both diseases. Our aim was to explore the genetic differences between individuals developing both these diseases (double autoimmunity) versus those with only one. We hypothesized that double autoimmunity individuals carry more of the genetic risk markers that are shared between the two diseases independently. SNPs were genotyped in loci associated with T1D (n = 42) and CeD (n = 28) in 543 subjects who developed double autoimmunity, 2,472 subjects with T1D only, and 2,223 CeD-only subjects. For identification of loci that were specifically associated with individuals developing double autoimmunity, two association analyses were conducted: double autoimmunity versus T1D and double autoimmunity versus CeD. HLA risk haplotypes were compared between the two groups. The CTLA4 and IL2RA loci were more strongly associated with double autoimmunity than with either T1D or CeD alone. HLA analyses indicated that the T1D high-risk genotype, DQ2.5/DQ8, provided the highest risk for developing double autoimmunity (odds ratio 5.22, P = 2.25 × 10−29). We identified a strong HLA risk genotype (DQ2.5/DQ8) predisposing to double autoimmunity, suggesting a dominant role for HLA. Non-HLA loci, CTLA4 and IL2RA, may also confer risk to double autoimmunity. Thus, CeD patients who carry the DQ2.5/DQ8 genotype may benefit from periodic screening of autoantibodies related to T1D.

Compromised quality of life in patients with both Type 1 diabetes mellitus and coeliac disease

Type 1 diabetes mellitus and coeliac disease are two chronic illnesses associated with each other. Both diseases and their treatments can seriously impair quality of life. The objective of the present study was to investigate health‐related quality of life in adult patients diagnosed with both Type 1 diabetes and coeliac disease and compare this with healthy control subjects and control subjects who have Type 1 diabetes only.

PROgnosticating COeliac patieNts SUrvivaL: the PROCONSUL score.

Introduction It has been shown that mortality rates of coeliac patients correlate with age at diagnosis of coeliac disease, diagnostic delay for coeliac disease, pattern of clinical presentation and HLA typing. Our aim was to create a tool that identifies coeliac patients at higher risk of developing complications. Methods To identify predictors of complications in patients with coeliac disease, we organised an observational multicenter case-control study based on a retrospective collection of clinical data. Clinical data from 116 cases (patients with complicated coeliac disease) and 181 controls (coeliac patients without any complications) were collected from seven European centres. For each case, one or two controls, matched to cases according to the year of assessment, gender and age, were selected. Diagnostic delay, pattern of clinical presentation, HLA typing and age at diagnosis were used as predictors. Results Differences between cases and controls were detected for diagnostic delay and classical presentation. Conditional logistic models based on these statistically different predictors allowed the development of a score system. Tertiles analysis showed a relationship between score and risk of developing complications. Discussion A score that shows the risk of a newly diagnosed coeliac patient developing complications was devised for the first time. This will make it possible to set up the follow-up of coeliac patients with great benefits not only for their health but also for management of economic resources. Conclusions We think that our results are very encouraging and represent the first attempt to build a prognostic score for coeliac patients.

Increase in bone mineral density in strictly treated Crohn's disease patients with concomitant calcium and vitamin D supplementation.

BACKGROUND AND AIMS Decreased bone mineral density (BMD) is common in Crohns disease (CD) patients. This paper reports on the prevalence of decreased BMD in a referral cohort study of CD-patients next to the change of BMD over time in relation with CD-associated clinical characteristics. METHODS 205 CD patients of a referral hospital were enrolled between January1998-January 2010 when measurement of BMD by dual X-ray absorptiometry (DXA) was available. Follow-up DXA scan was performed in subjects with known risk factors besides Crohn indicative for low BMD. Treatment of CD patients was according to a protocol which is comparable to the current (inter)national guidelines. In osteopenic patients, supplemental vitamin D (800 IU) and Calcium (500-1000 mg) were prescribed. RESULTS Mean BMD at baseline was 0.97 ± 0.16 gram/cm(2) in lumbar spine and 0.87 ± 0.12 gram/cm(2) in the total hip. At baseline, higher age and low Body Mass Index (BMI), were negatively correlated with BMD. Eighty-four patients underwent a second BMD assessment with a median interval period of 4 years (IQR 3-6). A mean annual increase of +0.76% (95%CI: -2.63%; +3.87%) in lumbar spine and +0.43% (95%CI: -2.65% ; +1.11%) in total hip was observed. CONCLUSIONS Higher age, male sex, low BMI, and a higher age at diagnosis of CD were associated with low BMD. Follow-up of BMD in CD patients showed a contraintuitive small increase of BMD at lumbar spine and total hip in CD patients only using supplemental vitamin D and calcium next to strict treatment of CD.

Advanced glycation end products (AGEs) and the soluble receptor for AGE (sRAGE) in patients with type 1 diabetes and coeliac disease.

BACKGROUND AND AIMS Advanced glycation end (AGE) products play a role in the progression of diabetic complications. Gluten-free diet (GFD) might affect AGE levels in patients who adhere to a GFD because of coeliac disease (CD). The aim of our study was to compare skin AGE levels and soluble receptor AGE levels (sRAGE) in patients with type 1 diabetes (T1DM) with (T1DM + CD) and without CD (T1DM - CD) and healthy controls. METHODS AND RESULTS We recruited 25 T1DM + CD and 25 T1DM - CD patients, matched for age, gender, diabetes duration, and glycaemic control alongside 25 healthy controls. We collected demographic, clinical and biochemical characteristics, including skin autofluorescence (AF), sRAGE and hs-CRP levels. The duration of T1DM in patients was 30 ± 14 (+CD) and 29 ± 14 years (-CD), whereas CD duration in T1DM + CD patients was 14 ± 10 years. Skin AF levels in T1DM patients were higher compared to healthy controls (2.5 ± 0.6 versus 1.9 ± 0.4, p < 0.01) and skin AF was independently associated with age (r = 0.72, p < 0.01). sRAGE levels were higher in T1DM - CD patients compared to healthy controls (1554 ± 449 versus 1309 ± 400, p = 0.049) and independently associated with creatinine levels (r = 0.32, p < 0.01). CONCLUSION Our study demonstrates that skin AGE and sRAGE levels are elevated in T1DM patients compared with healthy controls. No difference in skin AF or sRAGE levels between T1DM patients with or without CD were observed. The present study suggests that differences in microvascular complications between T1DM and T1DM + CD patients are not due to differences in skin AF or sRAGE levels.

Screening for coeliac disease in adult patients with type 1 diabetes mellitus: myths, facts and controversy

This review aims at summarizing the present knowledge on the clinical consequences of concomitant coeliac disease (CD) in adult patients with type 1 diabetes mellitus (T1DM). The cause of the increased prevalence of CD in T1DM patients is a combination of genetic and environmental factors. Current screening guidelines for CD in adult T1DM patients are not uniform. Based on the current evidence of effects of CD on bone mineral density, diabetic complications, quality of life, morbidity and mortality in patients with T1DM, we advise periodic screening for CD in adult T1DM patients to prevent delay in CD diagnosis and subsequent CD and/or T1DM related complications.

Antibody titers against food antigens decrease upon a gluten-free diet, but are not useful for the follow-up of (refractory) celiac disease.

Sascha Gross, Roy L.J. van Wanrooij, Greetje J. Tack, Kyra A. Gelderman, Sjoerd F. Bakker, Ingrid M.W. van Hoogstraten, Eskelina A. Neefjes-Borst, Marco W.J. Schreurs, Gerd Bouma, Chris J.J. Mulder, Boudewina M.E. von Blomberg and Hetty J. Bontkes, Medical Immunology Unit, Department of Pathology, Department of Gastroenterology, VU Medical Centre, Amsterdam and Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands