Heat-shock protein 70-1 and HLA class II gene polymorphisms associated with celiac disease susceptibility in Navarra (Spain)
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.
References (26)
- et al.
Celiac disease among Ashkenazi Jews from IsraelA study of a HLA class II alleles and their association with disease susceptibility
Hum Immunol
(1993) - et al.
HLA-DQ2-negative celiac disease in Finland and Spain
Hum Immunol
(1998) - et al.
HLA-linked genes acting as additive susceptibility factors in celiac disease
Hum Immunol
(1995) - et al.
Gluten induces an intestinal cytoquine response strongly dominanted, by interferon gamma in patients with celiac disease
Gastroenterology
(1998) Celiac sprue
N Engl J Med
(1991)- et al.
The primary association of celiac disease to a given HLA-DQ alpha/beta heterodimer explains the divergent HLA-DR association observed in various Caucasian populations
Tissue Antigens
(1990) - et al.
Molecular characterization of HLA class II genes in celiac patients of Latin American Caucasian origin
Tissue Antigens
(1994) - et al.
Genetics of Celiac Disease
Q J Med
(1996) Annu Rev Immunol
(2000)- et al.
A role for heat shock protein in antigen processing and presentation
Curr Top Microbiol Immunol
(1991)
Stress proteinsAutoimmunity and autoimmune disease
Curr Top Microbiol Immunol
Antibodies to 65 kDa and 70 kDa heat shock proteins in rheumatoid arthritis and systemic lupus erythematosus
Immunol Cell Biol
Colocalization of lymphocytes bearing gamma-delta T-cell receptor and heat shock protein HSP65+ oligodendrocytes in multiple sclerosis
Proc Natl Acad Sci USA
Cited by (20)
Gut epithelium inducible heat shock proteins: Protective properties and modulation by the microbiota and dietary factors
2016, Cahiers de Nutrition et de DietetiqueImmunology of celiac disease
2010, Gastroenterologia y HepatologiaIL6, IL10 and TGFB1 gene polymorphisms in coeliac disease: Differences between DQ2 positive and negative patients
2005, Allergologia et ImmunopathologiaHeat Shock Protein 70 Gene Polymorphism in Egyptian Patients with Type 2 Diabetes Mellitus, with and without Nephropathy
2020, Saudi Journal of Kidney Diseases and Transplantation