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American Journal of Clinical Nutrition 12/2012; · 6.67 Impact Factor
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Frederike Schmitz,
Jennifer M L Tjon,
Yuching Lai,
Allan Thompson,
Yvonne Kooy-Winkelaar,
Richard J L F Lemmers,
Hein W Verspaget, M Luisa Mearin,
Frank J Staal,
Marco W Schreurs,
Tom Cupedo,
Anton W Langerak,
Chris J Mulder,
Jeroen van Bergen,
Frits Koning
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ABSTRACT: OBJECTIVE: Refractory coeliac disease type II (RCDII) is a severe complication of coeliac disease (CD) characterised by aberrant intraepithelial lymphocytes (IELs) of unknown origin that display an atypical CD3(-)CD7(+)icCD3(+) phenotype. In approximately 40% of patients with RCDII these lymphocytes develop into an invasive lymphoma. In the current study we aimed to identify the physiological counterpart of these cells. DESIGN: RCDII cell lines were compared with T-cell receptor positive (TCR(+)) IEL (T-IEL) lines by microarray analysis, real-time quantitative PCR and flow cytometry. This information was used to identify cells with an RCDII-associated phenotype in duodenal biopsies from non-refractory individuals by multicolour flow cytometry. RESULTS: RCDII lines were transcriptionally distinct from T-IEL lines and expressed higher levels of multiple natural killer (NK) cell receptors. In addition to the CD3(-)CD7(+)icCD3(+) phenotype, the RCDII lines were distinguishable from other lymphocyte subsets by the absence of CD56, CD127 and CD34. Cells matching this surface lineage-negative (Lin(-)) CD7(+)CD127(-)CD34(-) phenotype expressed a functional interleukin-15 (IL-15) receptor and constituted a significant proportion of IELs in duodenal specimens of patients without CD, particularly children, and were also found in the thymus. In patients without CD, the Lin(-)CD7(+)CD127(-)CD34(-) subset was one of four subsets within the CD3(-)CD7(+)icCD3(+) population that could be distinguished on the basis of differential expression of CD56 and/or CD127. CONCLUSION: Our studies indicate that the CD3(-)CD7(+)icCD3(+) population is heterogeneous and reveal the existence of a Lin(-) subset that is distinct from T, B, NK and lymphoid tissue inducer cells. We speculate that this IL-15 responsive population represents the physiological counterpart of aberrant cells expanded in RCDII and transformed in RCDII-associated lymphoma.
Gut 07/2012; · 10.11 Impact Factor
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ABSTRACT: A food questionnaire (FQ) to assess gluten intake in infants 0 to 12 months old has been developed and validated (FQ-gluten), but an instrument to assess gluten intake in children 1 to 4 years is not available. Development and validation of such an instrument (FQ-gluten4) was the aim of the present study.
The FQ-gluten was adapted according to age-related food consumption. The results of this FQ-gluten4 were compared with the results of a 2-day food record.
Seventy-one parents filled in both instruments. The mean amount of gluten consumption calculated from the FQ-gluten4 was comparable with that of the food record, but significant differences were found in the amount of gluten intake in 1- to 2-year-old children and in the percentage of gluten from porridge among the 1- to 3-year-olds. The Blant-Altman limits of agreement with standard deviation of 2600 mg were -5118 to 5630 mg.
The new, short, standardized, validated, and easy-to-use FQ-gluten4 may be a useful instrument in the assessment of gluten intake in young children. Using this standardized method provides opportunity for better comparison of the results of gluten consumption in studies throughout the world. Furthermore, such an instrument can be used to quantify the gluten intake in individuals suspected to have celiac disease but in whom the diagnoses cannot be confirmed.
Journal of pediatric gastroenterology and nutrition 02/2012; 54(6):791-6. · 2.18 Impact Factor
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Yvonne Kooy-Winkelaar,
Menno van Lummel,
Antonis K Moustakas,
Joachim Schweizer, M Luisa Mearin,
Chris J Mulder,
Bart O Roep,
Jan W Drijfhout,
George K Papadopoulos,
Jeroen van Bergen,
Frits Koning
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ABSTRACT: Because susceptibility to celiac disease is associated strongly with HLA-DQ2 (DQA1*05/DQB1*02) and weakly with HLA-DQ8 (DQA1*03/DQB1*03), a subset of patients carries both HLA-DQ2 and HLA-DQ8. As a result, these patients may express two types of mixed HLA-DQ2/8 transdimers (encoded by DQA1*05/DQB1*03 and DQA1*03/DQB1*02) in addition to HLA-DQ2 and HLA-DQ8. Using T cells from a celiac disease patient expressing HLA-DQ8trans (encoded by DQA*0501/DQB*0302), but neither HLA-DQ2 nor HLA-DQ8, we demonstrate that this transdimer is expressed on the cell surface and can present multiple gluten peptides to T cell clones isolated from the duodenum of this patient. Furthermore, T cell clones derived from this patient and HLA-DQ2/8 heterozygous celiac disease patients respond to gluten peptides presented by HLA-DQ8trans, as well as HLA-DQ8, in a similar fashion. Finally, one gluten peptide is recognized better when presented by HLA-DQ8trans, which correlates with preferential binding of this peptide to HLA-DQ8trans. These results implicate HLA-DQ8trans in celiac disease pathogenesis and demonstrate extensive T cell cross-reactivity between HLA-DQ8 and HLA-DQ8trans. Because type 1 diabetes is strongly associated with the presence of HLA-DQ8trans, our findings may bear relevance to this disease as well.
The Journal of Immunology 11/2011; 187(10):5123-9. · 5.79 Impact Factor
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Gosia Trynka,
Karen A Hunt,
Nicholas A Bockett,
Jihane Romanos,
Vanisha Mistry,
Agata Szperl,
Sjoerd F Bakker,
Maria Teresa Bardella,
Leena Bhaw-Rosun,
Gemma Castillejo, [......],
Bozena Cukrowska,
Elena Urcelay,
Jose Ramon Bilbao, M Luisa Mearin,
Donatella Barisani,
Jeffrey C Barrett,
Vincent Plagnol,
Panos Deloukas,
Cisca Wijmenga,
David A van Heel
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ABSTRACT: 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.
Nature Genetics 11/2011; 43(12):1193-201. · 35.53 Impact Factor
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ABSTRACT: Subfertility has been reported as a long-term complication of unrecognized and/or untreated coeliac disease (CD); however, the results from studies on this topic are ambiguous. We aimed to determine the prevalence of unrecognized CD in subfertile male-female couples visiting a fertility clinic compared with the general population.
Subjects included 1038 male-female couples (n = 2076) who visited the fertility clinic of the Leiden University Medical Center in the Netherlands between 2003 and 2009. All consecutive patients were routinely, serologically screened, and those with positive test results for antibodies against IgA anti-tissue transglutaminase type 2 and IgA endomysial antibodies were considered to have unrecognized CD. Clinical data on gender, age, height, weight, diagnosis of subfertility, and previously diagnosed CD were collected from the clinical files. Subsequently, after serological screening, all patients were anonymized. The prevalence of unrecognized CD was compared with the one in the general adult population in the Netherlands (0.35%).
The prevalence of unrecognized CD in subfertile male-female couples was 0.48% (10/2076; 6 females and 4 males) and was not significantly more frequent compared with the general population. Compared with the control group, similar CD prevalences were found within the different subfertility categories separately: unexplained subfertility, anovulation, tubal pathology, and male factor (p = NS).
In our large study cohort of subfertile male-female couples, the prevalence of unrecognized CD is comparable to the general population in the Netherlands. No association was observed between CD and subfertility in the different subfertility categories and genders.
Scandinavian journal of gastroenterology 09/2011; 46(12):1423-8. · 2.08 Impact Factor
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ABSTRACT: Celiac disease (CD) is characterized by histologic alterations in small bowel biopsies. Circulating specific CD antibodies at the time of diagnosis and their disappearance after a gluten-free diet support the diagnosis of CD. We aimed to determine the behavior of the CD antibodies immunoglobulin A anti-tissue transglutaminase (anti-TG2) and immunoglobulin A endomysium (EMA) in children with CD after starting a gluten-free diet.
This was a retrospective multicenter study in the Netherlands between 2001 and 2009. Inclusion criteria were all newly diagnosed patients with CD younger than 19 years who had at least 1 anti-TG2 and/or EMA measurement before and after starting a gluten-free diet. Eight different anti-TG2 kits were used with substrates of guinea pig TG2 in 1 (Sigma) and 7 human-recombinant TG2: Varelisa and EliA Celikey Phadia-GmbH; Orgentec Diagnostica-GmbH; Diarect AG; Roboscreen GmbH; Aeskulisa Diagnostics; Binding Site Ltd. EMA was analyzed with indirect immunofluorescence tests. Statistical analyses were performed by using mixed-model repeated measurements and survival analysis.
There were 129 children with CD included (mean age: 5.6 years; SD ± 4.2). The mean concentration of anti-TG2 decreased significantly within 3 months after starting a gluten-free diet (P < .0001). The cumulative percentage of children who became negative for EMA after ½, 1, 1½, and 2 years was 31%, 60%, 74%, and 87%, respectively. For anti-TG2, a comparable trend was shown: 35%, 55%, 64%, and 78%, respectively.
Doctors taking care of children with CD should be aware that the mean concentration of anti-TG2 will show a 74% decrease (95% confidence interval: 69%-79%) after 3 months of gluten-free diet, and ∼80% of the children will be sero-negative for EMA and anti-TG2 after 2 years of the diet.
PEDIATRICS 08/2011; 128(3):547-52. · 4.47 Impact Factor
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Elisabet Einarsdottir,
Marianna R Bevova,
Alexandra Zhernakova,
Alienke Monsuur,
Lotta LE Koskinen,
Ruben van't Slot,
Chris Mulder, M Luisa Mearin,
Ilma R Korponay-Szabo,
Katri Kaukinen,
Kalle Kurppa,
Juha Kere,
Markku M|[auml]|ki,
Cisca Wijmenga,
P|[auml]|ivi Saavalainen
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ABSTRACT: Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P=0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P=3.6 × 10−5, OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility.Keywords: Celiac; linkage; association; genome-wide; 6q21-22
European Journal of HumanGenetics 02/2011; 19(6):682-686. · 4.40 Impact Factor
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Elisabet Einarsdottir,
Marianna R Bevova,
Alexandra Zhernakova,
Alienke Monsuur,
Lotta L E Koskinen,
Ruben van't Slot,
Chris Mulder, M Luisa Mearin,
Ilma R Korponay-Szabo,
Katri Kaukinen,
Kalle Kurppa,
Juha Kere,
Markku Mäki,
Cisca Wijmenga,
Päivi Saavalainen
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ABSTRACT: Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed fine mapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The 12 most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (P = 0.003, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (P = 3.6 × 10(-5), OR 0.76). The rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbors multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility.
European journal of human genetics: EJHG 02/2011; 19(6):682-6. · 3.56 Impact Factor
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ABSTRACT: Various genes may influence intestinal barrier function, including MAGI2, MYO9B, and PARD3, which are associated with celiac disease. Because direct measurement of intestinal permeability is difficult, antibodies against gliadin (AGA) and Baker's yeast (anti-Saccharomyces cerevisiae antibodies [ASCA]) can be used as an indirect test. The objective of this study was to investigate whether intestinal permeability, represented by AGA, was correlated with MAGI2, MYO9B, and PARD3. Analyses were performed in patients with Down syndrome, a population with suspected increased intestinal permeability. Correlations between AGA and ASCA were investigated. Patients with Down syndrome (n = 126) were genotyped for six single-nucleotide polymorphisms in MAGI2 (rs1496770, rs6962966, rs9640699), MYO9B (rs1457092, rs2305764), and PARD3 (rs10763976). An allele dosage association of these risk genes and AGA levels was performed. The correlation between AGA and ASCA was studied. A strong correlation was found between AGA and ASCA (p < 0.01). The patient group with one or more risk genotypes had lower mean AGA levels (trend test p = 0.007) and consisted of a larger number of patients with normal AGA levels (p = 9.3 x 10(-5)). Celiac-associated risk genotypes are associated with lower AGA values instead of elevated ones. Thus, other immunologic phenomena play a role in the increased prevalence of elevated AGA in patients with Down syndrome, possibly involving altered induction and/or maintenance of tolerance.
Human immunology 04/2010; 71(4):392-6. · 2.55 Impact Factor
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Patrick C A Dubois,
Gosia Trynka,
Lude Franke,
Karen A Hunt,
Jihane Romanos,
Alessandra Curtotti,
Alexandra Zhernakova,
Graham A R Heap,
Róza Adány,
Arpo Aromaa, [......],
Bozena Cukrowska,
Luigi Greco,
Susan L Neuhausen,
Ross McManus,
Donatella Barisani,
Panos Deloukas,
Jeffrey C Barrett,
Paivi Saavalainen,
Cisca Wijmenga,
David A van Heel
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ABSTRACT: We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.
Nature Genetics 02/2010; 42(4):295-302. · 35.53 Impact Factor
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Marieke J H Coenen,
Gosia Trynka,
Sandra Heskamp,
Barbara Franke,
Cleo C van Diemen,
Joanna Smolonska,
Miek van Leeuwen,
Elisabeth Brouwer,
Marike H Boezen,
Dirkje S Postma, [......],
Wieke H M Verbeek,
Victorien M Wolters,
Roderick H J Houwen, M Luisa Mearin,
David A van Heel,
Timothy R D J Radstake,
Piet L C M van Riel,
Cisca Wijmenga,
Pilar Barrera,
Alexandra Zhernakova
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ABSTRACT: Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune disorders which have commonalities in their pathogenesis. We aimed to replicate known RA loci in a Dutch RA population, and to investigate whether the effect of known RA and CD risk factors generalize across the two diseases. We selected all loci associated to either RA or CD in a GWAS and confirmed in an independent cohort, with a combined P-value cut-off P < 5 x 10(-6). We genotyped 11 RA and 11 CD loci in 1368 RA patients, 795 CD patients and 1683 Dutch controls. We combined our results in a meta-analysis with UK GWAS on RA (1860 cases; 2938 controls) and CD (767 cases; 1422 controls). In the Dutch RA cohort, the PTPN22 and IL2/IL21 variants showed convincing association (P = 3.4 x 10(-12) and P = 2.8 x 10(-4), respectively). Association of RA with the known CD risk variant in the SH2B3 was also observed, predominantly in the subgroup of rheumatoid factor-positive RA patients (P = 0.0055). In a meta-analysis of Dutch and UK data sets, shared association with six loci (TNFAIP3, IL2/IL21, SH2B3, LPP, MMEL1/TNFRSF14 and PFKFB3/PRKCQ) was observed in both RA and CD cohorts. We confirmed two known loci and identified four novel ones for shared CD-RA genetic risk. Most of the shared loci further emphasize a role for adaptive and innate immunity in these diseases.
Human Molecular Genetics 07/2009; 18(21):4195-203. · 7.64 Impact Factor
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ABSTRACT: Coeliac disease (CD) is associated with HLA-DQ2 and DQ8. The clinical picture is variable and certain human leucocyte antigen (HLA) DQ/DR combinations have a higher relative risk (RR) for CD than others. Moreover, the HLA-DQ gene-dose effect has an impact on the strength of the gluten-specific T-cell response and thus may correlate with clinical presentation and severity of CD. The aim of this study was to determine the correlation between HLA-DQ/DR-based genotypes and the variation in phenotypes of the disease.
A total of 113 non-related Caucasian children clinically diagnosed with CD during the period 1980-2003 with a known HLA type were included in the study. Patients were divided into four categories according to amount of disease expression predisposing to HLA-DQ2 or HLA-DQ8 molecules and the known RR of their HLA-DR/DQ type for CD: high (DR3DQ2 homozygous and DR3DQ2/DR7DQ2), substantial (DR3DQ2/DR5DQ7 and DR5DQ7/DR7DQ2), moderate (DR3DQ2-DR4DQ8 and DR3DQ2/DR*DQ*) and low (DR7DQ2/DR*DQ*, DR4DQ8- DR*DQ* and DR*DQ*- DR*DQ*). The clinical data and HLA genotypes of these patients were compared.
The 113 children were diagnosed with CD at a mean age of 4.6 years and boys were significantly older than girls when diagnosed (p=0.01). RR for having CD was highest for the high HLA-risk group (RR 8.1). With the exception of a greater frequency of abdominal distension and fewer non-gastrointestinal symptoms in the substantial HLA-risk group, there were no significant differences in clinical characteristics or degree of severity of the small-bowel histological findings between the children in the different HLA-risk groups.
No correlation was found between disease severity and a double HLA-DQ2 gene dose.
Scandinavian journal of gastroenterology 11/2008; 44(1):40-5. · 2.08 Impact Factor
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ABSTRACT: The development of a disease-specific, health-related, quality-of-life questionnaire for children ages 8 to 18 with celiac disease (CD), together with a parent-as-proxy version.
We used a focus-group method (bottom-up approach) to investigate the impact of CD on children's everyday lives and selected 24 items to create a preliminary disease-specific questionnaire. This questionnaire, together with the complementary generic quality-of-life questionnaire DUX-25, was sent to 756 children with CD in the Netherlands and was returned by 530 of them. With the help of statistical analyses (Cronbach alpha, factor analysis, Pearson correlation, Student t test, paired samples t test, and item response theory), we tested the psychometric performance of the 24 items.
We reduced the questionnaire to 12 items: the Celiac Disease DUX (CDDUX). The CDDUX has 3 subscales: "Communication" (3), "Diet" (6), and "Having CD" (3). This questionnaire proved to be reliable, valid, and feasible and able to discriminate between perception of severity in cases of CD as assessed by parents.
Children with a better perception of their own health status have a higher score on the CDDUX questionnaire. The whole group seems to have a lower quality of life than the healthy reference group on all domains of the DUX-25. The new disease-specific questionnaire CDDUX provides information about how children with CD think and feel about their illness. The questionnaire may enable researchers and clinicians to determine the consequences of this illness and the effects of clinical interventions on several aspects of daily living.
Journal of pediatric gastroenterology and nutrition 09/2008; 47(2):147-52. · 2.18 Impact Factor
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Karen A Hunt,
Alexandra Zhernakova,
Graham Turner,
Graham A R Heap,
Lude Franke,
Marcel Bruinenberg,
Jihane Romanos,
Lotte C Dinesen,
Anthony W Ryan,
Davinder Panesar, [......],
Daniel J Pennington,
David P Strachan,
Wendy L McArdle,
Charles A Mein,
Martin C Wapenaar,
Panos Deloukas,
Ralph McGinnis,
Ross McManus,
Cisca Wijmenga,
David A van Heel
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ABSTRACT: 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.
Nature Genetics 04/2008; 40(4):395-402. · 35.53 Impact Factor
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David Bernardo,
Ingrid M.W. van Hoogstraten,
Wieke H.M. Verbeek,
A. Salvador Peña, M. Luisa Mearin,
Eduardo Arranz,
José Antonio Garrote,
Rik J. Scheper,
Marco W.J. Schreurs,
Hetty J. Bontkes,
Chris J.J. Mulder,
B. Mary E. von Blomberg
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ABSTRACT: Introduction:A small proportion of coeliac disease (CD) patients become refractory (RCD) to a gluten-free diet (GFD) showing uncontrolled immune-mediated enteropathy. Some of these patients exhibit a high risk to develop enteropathy-associated T-cell lymphoma (EATL).Aim:The aim of the study was to find whether a lack of circulating homeostatic T cells, such as Treg, Tγδ+ or iNKT cells would be associated with the development of RCD or EATL.Patients and methods:We investigated in a total of 137 CD patients [28 untreated, 80 responsive to GFD and 29 RCD (14 type I and 15 type II)] and 73 age-matched healthy volunteers the frequency of Treg, Tγδ+ and iNKT lymphocytes by flow cytometric analysis of peripheral blood.Results:Circulating Tγδ+ cell and Treg frequencies in RCD were comparable to those in healthy controls. However, RCD patients had significantly reduced numbers of circulating iNKT cells, as compared to age-matched patients responding to a GFD. This reduction was similar in RCD patients with and without aberrant intraepithelial lymphocytes and in patients with EATL. Circulating iNKT cell numbers were not reduced in untreated coeliac patients. GFD treated patients had a significantly increased proportion of CD4+ iNKT cells.Conclusion:Follow-up studies are necessary to determine whether CD4+ iNKT cells control the immune response against gluten and their absence contributes to the progression to RCD and EATL.
Clinical Immunology 03/2008; · 4.05 Impact Factor
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David A van Heel,
Lude Franke,
Karen A Hunt,
Rhian Gwilliam,
Alexandra Zhernakova,
Mike Inouye,
Martin C Wapenaar,
Martin C N M Barnardo,
Graeme Bethel,
Geoffrey K T Holmes, [......],
Jill Swift,
Raymond J Playford,
William M McLaren, M Luisa Mearin,
Chris J Mulder,
Ross McManus,
Ralph McGinnis,
Lon R Cardon,
Panos Deloukas,
Cisca Wijmenga
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ABSTRACT: 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.
Nature Genetics 08/2007; 39(7):827-9. · 35.53 Impact Factor
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ABSTRACT: In light of the possibly preventive role of timing and amount of gluten in celiac disease, it would be helpful to have a questionnaire to assess the gluten intake in infants.
Development and validation of a food questionnaire to assess gluten consumption in healthy infants aged 0-12 months (FQ-gluten).
A food frequency questionnaire, previously developed for the Generation R study, was adapted for the assessment of gluten intake. The results of a 2-day food record (FR) were compared with the results of this FQ-gluten.
Eighty-seven parents filled in the FR and the FQ-gluten. The number of children who consume gluten and who are breast-fed is higher, reported in the FQ-gluten. The amount of gluten is comparable from the age of 3 up to 10 months, but at 11 and 12 months a higher gluten intake is reported using the FR, probably due to a larger variety of food products not detectable by the FQ-gluten. However, there is a high agreement in the food groups (Cohens' kappa=0.6-0.8).
This new, short, standardized, validated and easy to use FQ-gluten may be a useful instrument to assess gluten intake in infants, both at the individual and at the population level. The use of this method by investigators in other countries provides the opportunity for a better comparison of the results of gluten consumption in (co-operative) studies throughout different countries.
Clinical Nutrition 05/2007; 26(2):264-71. · 3.73 Impact Factor
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M Luisa Mearin
Current problems in pediatric and adolescent health care 04/2007; 37(3):86-105.
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ABSTRACT: To investigate the seroprevalence of Helicobacter pylori infection in young children from the general population in The Netherlands.
Determination of IgG antibodies against H. pylori, using an enzyme-linked immunosorbent assay technique [cutoff 0.32 Absorption Index (AI)], in serum from 1258 children who were 2-4 years of age. The serum was obtained from a serum bank of 6127 children who attended the community child healthcare centers in the Dutch province of Zuid-Holland.
In general, we found a seroprevalence of 1.2% of H. pylori infection, with a significant difference between the children with parents who were both Dutch (0.5%), and the children with at least one non-Dutch parent (2.6%) (P<0.001).
The prevalence of H. pylori infection in young infants in the general population in The Netherlands is low. Children with at least one non-Dutch parent form a risk group, however, for H. pylori infection in The Netherlands.
European Journal of Gastroenterology & Hepatology 04/2007; 19(3):213-6. · 1.76 Impact Factor
