Elsevier

Human Immunology

Volume 62, Issue 8, August 2001, Pages 821-825
Human Immunology

Heat-shock protein 70-1 and HLA class II gene polymorphisms associated with celiac disease susceptibility in Navarra (Spain)

https://doi.org/10.1016/S0198-8859(01)00277-4Get rights and content

Abstract

Heat shock proteins (HSP) are thought to play a role in the immune response making probable their contribution to celiac disease (CD). We studied the polymorphisms in the 5′ regulatory region of the HSP70-1 gene and performed genomic HLA-DQ and -DR typing in 128 CD patients and 94 healthy controls from Navarra (Spain). The frequency of the C allele of the HSP70-1, characterized by the intermediate electrophoretic mobility of DNA, was significantly increased among CD patients (64.5% vs 37.2%. p <1 × 10−7). When subjects were stratified by the HLA II genotype, differences were statistically significant between DR3-negative or DR3-DQB1∗02-negative CD patients and matched controls. Homozygosity for the DQB1∗02 allele was present in 48.4% of CD patients and 12.8% of controls (OR = 6.4; CI:3.1 to 13.8; p <1 × 10−7). Similar increased risk was observed for DQB1∗02/∗02, DRB1∗03/-, or DRB1∗03/07 patients. Furthermore, those individuals expressing the classical HLA alleles in CD (DQB1∗02/∗02, DRB1∗03/∗07) who also carried the HSP70-1 CC genotype were twelve times more likely to develop the disease than the matched controls. We therefore conclude that although HSP70-1 gene does not seem to be primarily associated with CD, it might be a component of the high risk haplotype, playing a role as an additional predisposing gene for the disease.

Introduction

Celiac disease (CD) is a gluten sensitive enteropathy characterized by small bowel mucosal atrophy. Ingestion of gluten containing cereals induces immunologically mediated intestinal injury in genetically susceptible individuals [1]. A significant part of the genetic component maps to the HLA class II region of the major histocompatibily complex (MHC). Most CD patients in European population present a DQαβ heterodimer encoded by the DQA1∗0501 and DQB1∗0201 alleles, in association with DR3 haplotype or DR7/DR5 haplotype, in cis or trans position, respectively [2]. However, the prevalence of HLA-DQ2 is high in the normal population and the frequencies of DQ2-negative celiac patients vary from 5% to 29% 3, 4, 5, suggesting, along with additional family studies, that other HLA and non-HLA genetic factor are likely to be required for the development of the disease 6, 7, 8.

Three genes of the heat shock protein (HSP) 70 family are located in the MHC class III region. These genes are of particularly interest since the HSPs seem to be involved in the antigen processing and presentation [9] and are thought to play a role in the pathogenesis in some autoimmune-like systemic disorders, such as systemic lupus eritematosus, rheumatoid arthritis, and multiple sclerosis 10, 11, 12. Having in mind that immune disturbances play a decisive role in the pathogenesis of CD [13], it is possible that HSPs might be involved in the development of this disorder. One previous study has shown an association of HSP70-2 gene polymorphism and CD [14]. However, they concluded that it was most probably due to linkage disequilibrium with HLA-DR3 allele. Here we extend the study analyzing the HSP70-1, HLA-DQ, and -DR gene polymorphism in our population of Navarra (Spain), in an attempt to investigate their possible contribution to CD.

Section snippets

Patients and methods

One hundred and twenty eight CD patients from Navarra were recruited for this study. The diagnosis of CD was established in all cases by demonstration of enteropathy with villous atrophy on small bowel biopsy and all patients fulfilled the revised ESP-GAN (European Society of Pediatric Gastroenterology and Nutrition) diagnostic criteria for CD [15]. The control group consisted of ninety four blood donors volunteers from this community. Samples of peripheral blood (10 ml) were taken from each

Results

As expected, frequency of DQB1∗02-positive individuals was significantly higher in celiac patients relative to controls (95.3% and 52.7%, respectively; p < 0.001). Similarly, DRB1∗03 and in a lower degree DRB1∗07 allelic frequencies were increased (Table 1) among individuals with this disorder (44.5% vs 18.6.2%, p <1 × 10−7 and 27.3% vs 19.7%, p = 0.06, respectively). A total of 62 (48.4%) DQB1∗02-positive celiac patients and 12 (12.8%) of matched controls were homozygous for this allele. All

Discussion

HSP70 genes have been previously tested in several diseases of the high degree HLA association group, like IDDM, rheumatoid arthritis, and Crohn disease 17, 18, 19, 20. However, due to a strong linkage disequilibrium within MHC, the role of these class III genes in disease association has not been neither ruled out nor clearly demonstrated. For CD, Partaner et al. [14] analyzed the HSP70-2 gene in 19 CD families and observed and that the gene frequencies in the affected haplotypes deviated from

Acknowledgements

We would like to thank all members of the celiac families who participated in this study. We are also grateful to I. Janices and E. Rodriguez for help in the recruitment of blood samples and to M.D. Martı́nez for her nursing assistance. This work was supported by a grant from the Departamento de Salud del Gobierno de Navarra.

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