IL6, IL10 and TGFB1 gene polymorphisms in coeliac disease: differences between DQ2 positive and negative patients

doi:10.1157/13080926

Allergologia et Immunopathologia

Volume 33, Issue 5, 2005, Pages 245-249

https://doi.org/10.1157/13080926 Get rights and content

Abstract

Predisposition to coeliac disease (CD) might be partially due to an individual pattern of hyper-inflammatory biased immune response. One of these patterns of intense response may be linked to the haplotype carrying HLA-DQ2 alleles and TNF −308A allele. However, 10 % of CD patients do not express the DQ2 heterodimer and these do not usually carry the TNF −308A allele. A similar response might be achieved by genes codifying other cytokines.

Objectives

To study biallelic polymorphisms in genes codifying for TNFα, IL10, IL6 and TGFβ1 in DQ2 negative CD patients and to compare the results with DQ2 positive patients and healthy controls, in order to establish whether any of these polymorphisms have a role in CD susceptibility.

Methods

TNF −308 (G > A), IL-6 −174 (G > C) and TGFB1 codon 10 (+ 869, T > C) and codon 25 (+ 915, G > C) polymorphisms and IL-10 haplotype of polymorphisms in positions −1082 (G > A), −819 (C > T) and −592 (C > A) were typed by a SSP-PCR technique.

Results

The distribution of allele frequencies for TNF −308 is different between DQ2 positive CD patients and controls and the same occurs for haplotype frequencies of the IL10 promoter (−1082, −819, −592): The frequencies of the TNF −308A allele (p = 0.027), TNF −308A carriers (p = 0.031) and of IL10GCC haplotype are increased (p = 0.013) in DQ2 positive CD patients. However, the IL6 −174 allele G is more frequent in DQ2 negative patients than in healthy controls (p = 0.018), DQ2 negative controls (p = 0,018), and DQ2 positive patients (p = 0.008).

Conclusions

DQ2 negative CD patients show an increased frequency of genotypes associated to IL6 high production. These were mainly allele G homozygous for the IL6 gene (−174) polymorphism. The IL6 −174GG genotype (homozygous) may be an additional risk marker for CD in DQ2 negative patients, representing an alternative susceptibility factor for CD when TNF −308A is negative.

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Celiac disease (CD) is an autoimmune/inflammatory condition triggered by dietary gluten intake in genetically predisposed individuals. Though associations with MHC class II HLA-DQ2 or -DQ8 are the primary and necessary genetic predisposition for CD, >97% of genetically predisposed individuals never develop CD.
Cytokines were measured in the serum of CD patients and controls. Possible associations with IL10 promoter variants were investigated. Cytokine expression from PBMCs was monitored in response to gluten exposure, or CD3/TCR complex stimulation in the absence or presence of recombinant IL-10.
Serum cytokines varied between patients with CD at the time of diagnosis, after dietary elimination of gluten, and healthy controls. Serum IL-17A reflected disease activity. Reduced IL-10 serum levels and altered IL-10 expression by PBMCs coincided with IL10 promoter haplotypes that encode for “low” IL-10 expression (ATA).
Increased prevalence of ATA IL10 promoter haplotypes and subsequently reduced IL-10 expression may be an immunological cofactor in individuals genetically predisposed for the development of CD. Resulting cytokine imbalances may be utilized as disease biomarkers in CD.
Interleukin-10 gene promoter polymorphisms in celiac patients from north-eastern Italy
2014, Human Immunology
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Our results are not in agreement with the study by Garrote et al. [15] that found an increased frequency of the GCC haplotype in Spanish HLA-DQ2 positive patients compared to controls. However, the study of Garrote et al. [15] included a reduced number of samples, 51 CD individuals and 99 healthy controls, while in our study a total of 565 CD patients and 576 healthy controls were tested. Our data are in accordance with other studies that lacked to find any association between IL10 polymorphisms and CD in two different Italian groups [16,17].
Celiac disease is a complex chronic intestinal disorder driven by an immune response against the gliadin fraction of gluten: many factors are involved in the pathogenesis of the disease, and among these Interleukin-10 could play an important role. In the present study, the −1082A>G, −819T>C and −592A>C IL10 functional polymorphisms were analyzed in 565 celiac patients and 576 healthy controls from north-eastern Italy, stratified for HLA class II celiac disease risk haplotypes. No significant differences were observed for the three IL10 polymorphisms distribution between celiac patients and controls with the exception of a slightly increased risk for the −1082A allele in HLA-DQ8 male individuals. Although our findings suggest that the IL10 genetic variants analyzed do not have a major role in the susceptibility to the development of celiac disease in north-eastern Italian patients, we think that the possible involvement of IL10 gene in CD should deserve further investigation and that large-scale studies are recommended to confirm our findings.
The IL6 -174G/C polymorphism is associated with celiac disease susceptibility in girls
2009, Human Immunology
Citation Excerpt :
Therefore, genetic polymorphisms modifying IL-6 levels could potentially contribute to CD susceptibility. However, few and relatively underpowered studies have been performed with this aim [7,8] and additional analysis are still necessary. We will evaluate the putative role of genetic IL6 polymorphisms in pediatric CD risk by performing a single-nucleotide polymorphism (SNP) tagging of the gene, with special attention to include the promoter -174G/C variation, which has been extensively studied because of its involvement in IL-6 transcriptional activity and plasma levels [9].
The aim of this paper was to study the role of IL6 and IL6R polymorphisms in celiac disease (CD) susceptibility. Because previous literature describes IL-6-related gender differences, sex-stratified analyses were performed. We undertook a case–control study with 374 pediatric CD patients and 853 healthy controls, all white Spaniards, and a family study using an independent sample including 303 trios for replication purposes. Three single-nucleotide polymorphisms tagging most of the variability of the IL6 gene (rs2069827, rs1800795 [-174G/C], and rs2069840) and one functional polymorphism in IL6R (rs8192284, Asp358Ala) were genotyped using TaqMan technology. Case–control comparisons were performed with the χ² test and family data were analyzed with the transmission disequilibrium test. No association was observed between any tested polymorphism and overall CD. However, after sex stratification, we found that the IL6 promoter variant -174C increases the risk of developing CD specifically in female patients. This effect was observed both in the case–control and in the family studies (considering girls included in both studies vs boys: p = 0.021, odds ratio [OR] = 1.31, 95% confidence interval [CI] 1.03–1.66; and vs controls: p = 0.003, OR = 1.30, 95% CI 1.09–1.55). The functional -174G/C IL6 polymorphism seems to influence CD susceptibility in girls. The gender-specific role of IL-6 in this pathology must be further investigated.
Interleukin 6 -174(G>C) gene polymorphism is related to celiac disease and autoimmune thyroiditis coincidence in diabetes type 1 children
2008, Diabetes Research and Clinical Practice
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Some limitation of the conduced study related to the small number of DM1 patients with concomitant celiac disease has to be acknowledged. However, also a spanish study [26] that was carried out on a larger group of 51 children diagnosed with celiac disease but having no other coexistent autoimmune disorder showed the również significant role played by the IL-6 gene −174(G>C) polymorphism in the pathogenesis of celiac disease. These studies have shown statistically higher incidence of IL-6 gene −174GG genotype (p = 0.008) and significantly lower frequency of IL-6 gene −174C allele (p = 0.025) in celiac patients negative for DQ2 heterodimer.
The aim of the study was to assess the relationship between IL-6 gene polymorphism at −174(G>C) and the coincidence of celiac and autoimmune thyroid diseases with type 1 diabetes mellitus (DM1) in children. 200 children with DM1 aged 13.23 ± 3.54 years and 172 healthy controls were analyzed. The IL-6 gene −174(G>C) polymorphism at the promoter region of the gene was analyzed by the PCR–RFLP method. The genotype distribution was significantly different in diabetic children as compared to the healthy controls (p = 0.01). In DM1 patients GC heterozygotes were the most common (52.5%), while CC homozygotes accuted for 29% and GG homozygotes only for 18% of cases. In contrast, GG homozygotes were much more frequent among healthy children (31%). Besides, the GG homozygotes were significantly more frequent among diabetic children with celiac disease (p = 0.04) in relation to those without autoimmune complications. In children with autoimmune thyroiditis, the distribution of the IL-6 genotypes was similar to that seen in diabetic patients without autoimmune complications (p = 0.24). The results of our study suggest that the diabetic children, who have IL-6 gene −174GG genotype may have an increased risk for celiac disease development.
The simultaneous presence of IL-1B and TNFA two-positions risk haplotypes enhances the susceptibility for celiac disease
2008, Cytokine
To assess the joint contribution of interleukin 1 beta (IL-1B) and tumor necrosis factor alpha (TNFα) to the genetic risk of developing celiac disease (CD), we analyzed four biallelic polymorphisms of TNFA and IL-1B genes in 228 patients and 244 healthy controls. The individual contribution of TNFA −308A and IL-1B −511C alleles was weak (OR 1.47 and 1.66, respectively) and was null for TNFA −238 A/G and IL-1B +3953 C/T single nucleotide polymorphisms (SNPs). Due to the potential linkage disequilibrium between TNFA, human leukocyte antigen (HLA) -DQA1 and HLA-DQB1 genes, only individuals carrying DQ2 antigen (DQ2-positive) were considered to perform haplotype analyses. Two-position risk haplotypes were first defined by the combined presence of −511C and +3953T alleles for IL-1B (OR 9.402) or −308A and −238A alleles for TNFA (OR 15.389). The TNFA/IL-1B combined haplotype-stratified association analysis showed that the simultaneous presence of TNFA risk and IL-1B non-risk haplotypes (OR 13.32) but not TNFA non-risk and IL-1B risk haplotypes (OR 0.71) is associated with CD. Interestingly, our data suggest that the coexistence of both risk haplotypes seems to work synergistically (OR 29.59), which enhances the risk of developing CD.
Human intestinal αβ IEL clones in celiac disease show reduced IL-10 synthesis and enhanced IL-2 production
2006, Cellular Immunology
Citation Excerpt :
Functional IL-10 promoter single-nucleotide polymorphisms associated to the level of production of the cytokine have been described [27] but typing of our three donors (EC9, EC41 and NEC40) showed that neither the patients nor the control carried the high producing genotype (L. Fainboim, unpublished data). On the other hand, no correlation of such polymorphisms with celiac disease susceptibility has been demonstrated [28,29]. The in situ regulatory role of IL-10 is suggested by many data.
Celiac disease is a gluten-induced T-cell mediated autoimmune process that results in the destruction of the intestinal mucosa and is associated with an expansion of CD8⁺ CD103⁺ TCRαβ intraepithelial lymphocytes (IELs) in the damaged epithelium. The role of this IEL population in the pathology is unknown. The aim of this work was to compare the cytokine profile and the cytotoxicity pattern from CD8⁺ IEL clones isolated from celiac (CD) and non-celiac (NCD) biopsies. We report that the number of IL-10 producing CD clones was significantly lower (26%) than that obtained from the NCD sample (62%). Instead, IL-2 was produced by more CD (44%) than NCD clones (26%). Cytotoxicity patterns against intestinal epithelial cell lines suggest different functional subsets of CD8⁺ IELs. CD clones capable of high cytotoxicity produced IL-2 whereas most cytotoxic NCD IELs produced IL-10. This clonal analysis indicates that an impaired immune regulation in celiac mucosa may be partially attributed to the low generation of regulatory CD8⁺ IELs that produce IL-10.

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Original articlesIL6, IL10 and TGFB1 gene polymorphisms in coeliac disease: differences between DQ2 positive and negative patients

Abstract

Objectives

Methods

Results

Conclusions

Autoimmun Rev

Hum Immunol

Hum Immunol

Mol Genet Metab

Hum Immunol

Am J Gastroenterol

Hum Immunol

TNF alpha and LT alpha gene polymorphisms as additional markers of celiac disease susceptibility in a DQ2-positive population

Immunogenetics

Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease

Scand J Immunol

An investigation of polymorphism in the interleukin-10 gene promoter

Eur J Immunogenet

Original articles
IL6, IL10 and TGFB1 gene polymorphisms in coeliac disease: differences between DQ2 positive and negative patients