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The latest Gastroenterology, Oct 2003, features an editorial on potential
treatments for CD plus 2 research articles: one on T-cell activating
peptide sequence similarities found in gluten, rye, barley, and, less so,
with oat peptides; the other on new genetic CD markers. The full-text of
the editorial is free.
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Gastroenterology, Oct 2003, Vol 125, No 4, p1264-67
Editorial -
Celiac disease: A future without gluten-free diet??
Mélika Benahmed, Jean-Jacques Mention, Tamara Matysiak-Budnik, Nadine Cerf-
Bensussan
Free full-text (Past this address together on one line):
http://www2.gastrojournal.org/scripts/om.dll/serve?
article=as0016508503012484&nav=full
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Gastroenterology, Oct 2003, Vol 125, No 4, p1105-13
Characterization of cereal toxicity for celiac disease patients based on
protein homology in grains
L.Willemijn Vader, Dariusz T. Stepniak, Evelien M. Bunnik, Yvonne M.C.
Kooy, Willeke De Haan, Jan Wouter Drijfhout, Peter A. Van Veelen, Frits
Koning
Department of Immunohematology and Blood Transfusion, Leiden University
Medical Center, Leiden, The Netherlands.
Supported by grants from the European Community (BHM4-CT98-3087 and QLK1-
2000-00657) and the Stimuleringsfonds Voedingsonderzoek LUMC.
Abstract
Background & Aims: Celiac disease is caused by T-cell responses to wheat
gluten-derived peptides. The presence of such peptides in other widely
consumed grains, however, has hardly been studied.
Methods: We have performed homology searches to identify regions with
sequence similarity to T-cell stimulatory gluten peptides in the available
gluten sequences: the hordeins of barley, secalins of rye, and avenins of
oats. The identified peptides were tested for T-cell stimulatory
properties.
Results: With 1 exception, no identical matches with T-cell stimulatory
gluten peptides were found in the other grains. However, less stringent
searches identified 11 homologous sequences in hordeins, secalins, and
avenins located in regions similar to those in the original gluten
proteins. Seven of these 11 peptides were recognized by gluten-specific T-
cell lines and/or clones from patients with celiac disease. Comparison of T-
cell stimulatory sequences with homologous but non-T-cell stimulatory
sequences indicated key amino acids that on substitution either completely
or partially abrogated the T-cell stimulatory activity of the gluten
peptides. Finally, we show that single nucleotide substitutions in gluten
genes will suffice to induce these effects.
Conclusions: These results show that the disease-inducing properties of
barley and rye can in part be explained by T-cell cross-reactivity against
gluten-, secalin-, and hordein-derived peptides. Moreover, the results
provide a first step toward a rational strategy for gluten detoxification
via targeted mutagenesis at the genetic level.
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Gastroenterology, Oct 2003, Vol 125, No 4, p1032-41
A major non-HLA locus in celiac disease maps to chromosome 19
Martine J. Van Belzen, Jos W.R. Meijer, Lodewijk A. Sandkuijl, Alfons F.J.
Bardoel, Chris J.J. Mulder, Peter L. Pearson, Roderick H.J. Houwen, Cisca
Wijmenga
Departments of Medical Genetics, University Medical Center Utrecht,
Utrecht, The Netherlands; Pediatrics, University Medical Center Utrecht,
Utrecht, The Netherlands; Department of Hepatogastroenterology, Rijnstate
Hospital, Arnhem, The Netherlands.
Supported by a grant from the Dutch Digestive Diseases Foundation (WS 97-44
to C.W. and R.H.J.H.).
This study is dedicated to the memory of Lodewijk Sandkuijl (1953-2002),
who died shortly after its completion. He was an inspiration to us and was
a world expert on biostatistics.
Abstract
Background & aims: The pathogenesis of celiac disease is still unknown
despite its well-known association with human leukocyte antigen (HLA)-DQ2
and DQ8. It is clear that non-HLA genes contribute to celiac disease
development as well, but none of the previous genome-wide screens in celiac
disease have resulted in identification of these genes.
Methods: We, therefore, performed a 2-stage, genome-wide screen in 101
affected sibpairs from 82 Dutch families who met strict diagnostic
criteria. The small intestinal biopsy samples, on which the original celiac
disease diagnoses had been based, showed a Marsh III lesion in all patients
on reevaluation by 1 pathologist. For association analysis of markers in
regions linked to celiac disease, 216 independent MIII patients and 216 age-
and sex-matched controls were available.
Results: As expected, highly significant linkage to the HLA-region was
detected (multipoint maximum lod score [MMLS] = 8.14). More importantly,
significant linkage was also present at 19p13.1 (MMLS = 4.31), with the
peak at marker D19S899. Moreover, this marker was also significantly
associated with celiac disease in the case-control study (corrected P =
0.016). Furthermore, we identified suggestive linkage to 6q21-22, which is
~70 cM downstream from the HLA region (MMLS = 3.10).
Conclusions: Significant linkage of celiac disease to chromosome region
19p13.1 was detected in our genome-wide screen. These results were
confirmed by the association of D19S899 to celiac disease in an independent
case-control cohort. Furthermore, we identified a possible second celiac
disease locus on chromosome region 6q21-22.
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