TY - JOUR
T1 - The interferon gamma gene in celiac disease
T2 - Augmented expression correlates with tissue damage but no evidence for genetic susceptibility
AU - Wapenaar, Martin C.
AU - Van Belzen, Martine J.
AU - Fransen, Justin H.
AU - Fariña Sarasqueta, Aranzazu
AU - Houwen, Roderick H.J.
AU - Meijer, Jos W.R.
AU - Mulder, Chris J.J.
AU - Wijmenga, Cisca
N1 - Funding Information: We wish to thank the celiac disease patients and their families for participating in this study. Results of the HLA-typing were kindly provided by Dr. B. Crusius (Laboratory of Immunogenetics, VU Medical Center, Amsterdam). Alfons Bardoel and Ineke Lavrijsen assisted in genotype ascertainment, and Lude Franke in the statistical analysis of the expression data (members of Department of Biomedical Genetics, UMC Utrecht). We thank Dr. F. Koning for critically reading this report and are indebted to Jackie Senior for editing the manuscript. This study was supported by grants WS 00-13 and WS 97-44 from the Dutch Digestive Diseases Foundation (MLDS).
PY - 2004/9
Y1 - 2004/9
N2 - Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-γ), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-γ, either as a genetic factor in the etiology, or as a facilitator of disease initiation/progression. Duodenal biopsies were sampled across distinct histopathological stages of the disease, including refractory CD (RCD), and used to determine IFN-γ gene (IFNG) expression by real-time RT-PCR. INFG expression correlated with the extent of tissue restructuring, reaching a 240-fold higher expression in total villous atrophy compared to healthy tissue. CD and RCD patients with similar lesions had comparable expression levels. Interestingly, patients in complete remission still had 7.6-fold residual over-expression. An INFG marker was tested in three cohorts of Dutch patients for both genetic linkage and association. Linkage analysis yielded no significant scores for IFNG or its flanking markers. In addition, IFNG allele frequencies were not differently distributed between cases and controls. Likewise, all alleles were randomly transmitted to affected children in parents-case trios. There is no evidence for IFNG as a predisposing gene in CD, despite its enhanced expression in patients in complete remission.
AB - Celiac disease (CD) is a complex genetic disorder characterized by gluten intolerance. The Th1 immune response, with a key position for interferon gamma (IFN-γ), is an important determinant of intestinal remodeling in CD. We aimed at further ascertaining the role of IFN-γ, either as a genetic factor in the etiology, or as a facilitator of disease initiation/progression. Duodenal biopsies were sampled across distinct histopathological stages of the disease, including refractory CD (RCD), and used to determine IFN-γ gene (IFNG) expression by real-time RT-PCR. INFG expression correlated with the extent of tissue restructuring, reaching a 240-fold higher expression in total villous atrophy compared to healthy tissue. CD and RCD patients with similar lesions had comparable expression levels. Interestingly, patients in complete remission still had 7.6-fold residual over-expression. An INFG marker was tested in three cohorts of Dutch patients for both genetic linkage and association. Linkage analysis yielded no significant scores for IFNG or its flanking markers. In addition, IFNG allele frequencies were not differently distributed between cases and controls. Likewise, all alleles were randomly transmitted to affected children in parents-case trios. There is no evidence for IFNG as a predisposing gene in CD, despite its enhanced expression in patients in complete remission.
KW - Celiac disease
KW - Gene expression
KW - Genetics
KW - Interferon gamma
KW - Intestinal mucosa
UR - http://www.scopus.com/inward/record.url?scp=8444221894&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jaut.2004.05.004
DO - https://doi.org/10.1016/j.jaut.2004.05.004
M3 - Article
C2 - 15324937
SN - 0896-8411
VL - 23
SP - 183
EP - 190
JO - Journal of autoimmunity
JF - Journal of autoimmunity
IS - 2
ER -