Interleukin 6 −174(G>C) gene polymorphism is related to celiac disease and autoimmune thyroiditis coincidence in diabetes type 1 children

doi:10.1016/j.diabres.2008.07.004

Diabetes Research and Clinical Practice

Volume 82, Issue 1, October 2008, Pages 108-112

https://doi.org/10.1016/j.diabres.2008.07.004 Get rights and content

Abstract

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.

Introduction

The ethiopathogenesis of the diabetes mellitus type 1 (DM1) is not yet fully understood, but the recently emerging data provide more evidence that the combination of environmental and genetic factors play an important role in the process of overcoming the tolerance to self-antigens and inducing cellular and humoral autoimmune responses against some of the structures of the β-cells producing insulin [1], [2]. Growing amount of data supports the thesis that the intensity of the immunologic response is genetically regulated and related to the function of cytokine-coding genes [3]. Specific genotypes of the cytokine genes regulate the level of their synthesis [4] and therefore their identification might be of great help in assessing the genetic risk of the development of an autoimmune disease [5], [6], [7]. So far only a few papers were published on the role of the IL-6 gene polymorphisms in the pathogenesis of DM1 [3], [8], and not many works were published with respect to other autoimmune disorders: including juvenile arthritis and osteoporosis [5], [9], [10]. Still, in the existing publications no information with respect to the IL-6 gene −174(G>C) polymorphism in celiac disease and autoimmune thyroiditis in children with DM1 is available.

According to various data, 1.0–10.4% of children diagnosed with DM1 develop celiac disease, and 20–30% present signs of autoimmune thyroiditis—the data vary according to the age of the analyzed group and diagnostic methods [11], [12], [13], [14]. One of the arguments suggesting the existence of common predisposition factors for the development of celiac disease, autoimmune thyroiditis and DM1 comes from the fact that all of these disorders correlate with the same genotype—the HLA-DQA1*0501, DQB1*0201 heterodimer [15]. However, it remains unresolved why there is a difference in the frequency of the coincidence of autoimmune disorders in the group of patients with DM1 having the same HLA genotype. Accordingly, the correlation of the incidence of autoimmune disorders with the HLA genotype only partially provides for genetic predisposition and similarities in the pathogenesis of the auto-aggression reactions.

On the account of the aforementioned, the objective of this study was to assess the frequency of the IL-6 gene −174(G>C) polymorphism in children diagnosed with DM1 and to analyze the putative correlation between the IL-6 gene −174(G>C) polymorphism and incidence of the concomitant celiac disease and/or autoimmune thyroiditis in diabetic children.

Section snippets

Subjects and methods

The study was conducted on a group of 200 children with long-standing DM1 (93 boys, 107 girls) aged 13.23 ± 3.54 years; the duration of the disease ranged 4.38 ± 3.22 years, recruited from patients of the Outpatient Diabetology Clinics at the Institute of Pediatrics, Hematology, Oncology and Endocrinology at the Medical University of Gdańsk, Poland. The diagnosis of DM1 was carried out in accordance with the American Diabetes Association Criteria [16]. Patients were treated using humanized insulin.

IL-6 genotypes in diabetic children

Table 1 summarizes the occurrence of the IL-6 genotypes at the −174GC locus both in children diagnosed with DM1 and healthy controls. It appeared that frequencies of the genotypes varied significantly between these groups (p = 0.01). The most frequent group of diabetic children had IL-6 gene −174GC genotype (n = 105; 52.5%), followed by −174C genotype (n = 59; 29%), while the least frequent was IL-6 gene −174GG genotype (n = 36; 18%). In contrast, the IL-6 gene −174GG genotype was much more frequent in

Discussion

In the available literature little is published with respect to the role of IL-6 gene −174(G>C) polymorphism as a predisposing factor for DM1 development, and a few conducted studies provide contradictory results obtained mostly on adult group of patients. Jahromi et al. showed statistically significant increase in the frequency of IL-6 gene −174GG genotype in relation to the IL-6 gene −174CC in adult patients diagnosed with DM1 [8]. On the other hand Herbert et al. presented results indicating

Conflicts of Interest

None.

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Cited by (13)

Genetic variations in interleukin 6 rs1800795 polymorphism and the association with susceptibility to Hashimoto's thyroiditis
2017, Meta Gene
Citation Excerpt :
Myśliwiec M et al., investigated the relationship between IL-6 gene polymorphism at rs1800795 and the coincidence of celiac and autoimmune thyroid diseases with type 1 diabetes mellitus (DM1) in children. The results of this study suggested that the diabetic children, who have IL-6 gene -174 GG genotype may have an increased risk for celiac disease development (Myśliwiec et al., 2008). Ozgen AG et al., showed that The rs1800795 polymorphism in the IL-6 gene is associated with increased risk of papillary thyroid carcinoma (PTC) in Turkish patients (Ozgen et al., 2009).
Hashimoto's disease is a polygenic disorder with complex etiopathogenesis. The imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. We aimed to evaluate the relation between 174 promoter region of the interleukin 6 rs1800795 gene polymorphism in patients with Hashimoto's thyroiditis (HT). We studied 110 HT patients and 110 healthy controls. The evaluation of genotype for interleukin 6 rs1800795 gene polymorphism were performed by using PCR-RFLP method. The genotype of IL6 distribution did differ between the control group (CC 17.3%, GC 78.2%, GG 4.5%) and the HT patients (CC 29.1%, GC 46.4%, GG 24.5%) (p < 0.001). The frequency of the polymorphic G allele was similar for the group with HT patients as the control group with 47.7% and 43.6%, respectively (p > 0.05). Our results indicate that interleukin 6 rs1800795 polymorphism may be associated with susceptibility to HT in Turkish Patients. It is necessary to confirm the results and determine the underlying pathogenic mechanisms in further studies.
Lack of association of IL-6 polymorphism with rheumatoid arthritis/type 1 diabetes: A meta-analysis
2013, Joint Bone Spine
Citation Excerpt :
Recently, increasing studies have discussed about the polymorphism and RA/T1D. However, different findings exist [9–20]. Arman et al. [9] found no significant association between RA and –174 genotype distribution and allele frequency in Turkish population.
The aim of this study was to determine whether the interleukin (IL)-6 –174 single nucleotide polymorphism confers susceptibility to rheumatoid arthritis (RA) and type 1 diabetes (T1D) in multiple ethnic populations.
A meta-analysis was conducted on the association between the IL-6 –174 polymorphism and RA/T1D susceptibility, using fixed and random effects models.
Thirteen studies were included in the meta-analysis: RA: seven studies, including six European and one Asian population; T1D: six studies, including five European and one South American population. There was no significant association both in allele and genotype comparisons between the IL-6 –174 polymorphism and RA/T1D in all study subjects. Moreover, meta-analysis stratified by ethnicity indicated no significant association between the gene and RA/T1D.
This meta-analysis suggests that the IL-6 –174 polymorphism might not confer susceptibility to RA/T1D.
Lack of association of IL-6 gene polymorphism with rheumatoid arthritis and type 1 diabetes: A meta-analysis
2013, Revue du Rhumatisme (Edition Francaise)
Le but de cette étude était de déterminer si le polymorphisme nucléotidique de l’interleukine (IL)-6-174 confère une susceptibilité à la polyarthrite rhumatoïde (PR) et au diabète de type 1 (DT1) dans des populations multiethniques.
Une méta-analyse fut conduite sur l’association entre le polymorphisme IL-6-174 et la susceptibilité PR/DT1 en utilisant des modèles à effets fixes et aléatoires.
Treize études furent incluses dans la méta-analyse : PR sept études, incluant six populations européennes et une asiatique ; DT1 : six études incluant cinq populations européennes et une sud-américaine. Il n’y avait pas d’association significative dans les comparaisons, à la fois entre les allèles et les génotypes, entre le polymorphisme IL-6-174 et les PR/DT1 chez les sujets de toutes les études. De plus, la méta-analyse stratifiée par ethnies indique l’absence d’association entre le gène et les PR/DT1.
Cette méta-analyse suggère que le polymorphisme génétique IL-6-174 pourrait ne pas conférer une prédisposition à la PR et au DT1.
The lack of association between interleukin-6 gene -174 G/C polymorphism and the risk of type 1 diabetes mellitus: A meta-analysis of 18,152 subjects
2013, Gene
Citation Excerpt :
Most studies reported that IL-6 gene − 174 C allele was associated with the risk of T1DM (Cooper et al., 2007; Pérez-Bravo et al., 2011; Settin et al., 2009). Several other studies demonstrated that G allele was associated with the development of T1DM (Jahromi et al., 2000; Myśliwiec et al., 2008). However, the studies of Myśliwska et al. and Javor et al. suggested that IL-6 gene − 174 G/G genotype appeared to be a protective factor for T1DM (Javor et al., 2010; Myśliwska et al., 2009).
Epidemiological studies have evaluated the association between interleukin-6 (IL-6) gene − 174 G/C polymorphism and type 1 diabetes mellitus (T1DM) risk, but results of different studies have been inconsistent. The present meta-analysis was therefore designed to clarify these controversies. PubMed, Embase and Web of Science were searched from the first available year to March 25, 2012, as well as hand searching of the references of identified articles were performed. All studies investigating the association between IL-6 gene − 174 G/C polymorphism and T1DM risk were included. Data analyses were carried out by Review Manager 5.1.2 and Stata 11.0. Seven studies were included in the final meta-analysis, covering a total of 9697 T1DM cases and 8455 controls. The results showed no evidence for significant association between IL-6 gene − 174 G/C polymorphism and T1DM risk (for C/C + C/G vs. G/G: OR = 1.30, 95% CI = 0.84–2.00, p = 0.24; for C/C vs. C/G + G/G: OR = 1.10, 95% CI = 0.75–1.60, p = 0.63; for C/C vs. G/G: OR = 1.34, 95% CI = 0.75–2.42, p = 0.33; for C allele vs. G allele: OR = 1.16, 95% CI = 0.88–1.53, p = 0.30). In addition, the similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests that IL-6 gene − 174 G/C polymorphism is not associated with T1DM risk. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.
The combination of Interleukin-10 - 1082 and tumor necrosis factor α - Interleukin-6 - 174 genes polymorphisms suggests an association with susceptibility to Hashimoto's thyroiditis
2012, International Immunopharmacology
Citation Excerpt :
Elevated TNFα and IL-6 levels in serum and diminished IL-10 synthesis in peripheral blood mononuclear cells (PBMC) have been reported in patients with autoimmune thyroid disease [7–10]. Several single nucleotide polymorphisms (SNPs) in the regulatory regions of TNFα, IL-6 and IL-10 have been implicated to modulate the risk of autoimmune diseases, possibly by influencing the expression of the protein [11–20] and could be critical to the etiology of HT. Therefore, in the present study, we aimed to investigate whether TNFα G-308A, IL-6 G-174C and IL-10 G-1082A polymorphisms could predispose to HT, and to evaluate the possible relationship between genotypes and clinical/biochemical characteristics of HT.
The etiopathogenesis of Hashimoto's thyroiditis (HT) has not been clearly elucidated although the role of chronical inflammation and endothelial dysfunction has been established. The imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. The aim of the present study was to investigate whether cytokine gene polymorphisms are associated with HT, and to evaluate the relationship between genotypes and clinical/laboratory manifestation of HT.
Tumor necrosis factor α (TNFα) G-308A (rs 1800629), interleukin-6 (IL-6) G-174C (rs 1800795) and IL-10 G-1082A (rs 1800896) single nucleotide polymorphisms (SNPs) in DNA from peripheral blood leukocytes of 190 patients with HT and 231 healthy controls were investigated by real-time PCR combined with melting curve analysis using fluorescence-labeled hybridization probes.
There was no notable risk for HT afflicted by TNFα − 308, IL-6 − 174 and IL-10 − 1082 polymorphisms alone. However, carriers of variant alleles of both IL-10 − 1082 and TNFα − 308 polymorphisms had four-fold times higher risk for HT in comparison with non-carriers. Additionally, concomitant presence of both mutant IL-10 − 1082 A and IL-6 − 174 C alleles raised three-fold the HT risk.
Our results suggest that the combined effects of TNFα − 308, IL-6 − 174 and IL-10 − 1082 variant alleles may be more decisive to induce functional differences and modify the risk for HT.
Bone involvement in clusters of autoimmune diseases: Just a complication?
2010, Bone
Citation Excerpt :
Clustering of these diseases in the same individual is not unusual, suggesting that common immune mechanisms may facilitate immune mediated processes. A shared genetic background might explain this association [2,3]. Routine screening for ATD or CD, that often occur asymptomatic or oligosymptomatic, allows an early diagnosis and a possible prevention of their potential negative effects, by replacing normal thyroid function, if altered, or adopting a strict gluten-free regimen [4].
Bone loss, described in individual groups of patients with Type 1 diabetes (T1D), autoimmune thyroid disease (ATD) or celiac disease (CD) is usually viewed as a complication of these diseases. There is increasing evidence that alterations in the immune system may directly affect bone mass. Clustering of autoimmune diseases in the same individual might predispose to higher risk of osteopenia due to imbalance in immune regulation. The aim of this study was to evaluate bone involvement in clusters of the most common autoimmune diseases (T1D, ATD and CD) in children.
The study was performed at a tertiary care center for the care of pediatric diabetes. One-hundred-two patients with T1D alone or associated with ATD and/or CD were studied; 13 patients had cluster of three autoimmune diseases. Amplitude-dependent speed of sound (AD-SoS) was measured by phalangeal quantitative ultrasound and expressed as standard deviation score (SDS). AD-SoS SDS < −2 was considered indicative of osteopenia.
Osteopenia was equally distributed among children with T1D alone (8.1%), T1D associated with ATD (7.7%) or CD (10.3%), while it was 53.8% in patients presenting with three autoimmune diseases. Poor compliance to gluten-free diet increased osteopenia to 18.8% in patients with T1D and CD and 80% in patients with three autoimmune disorders. No difference among groups was found with regard to gluco-metabolic control, calcium metabolism, thyroid function.
In conclusion bone impairment in multiple autoimmune diseases might be considered not only a complication due to endocrine or nutritional mechanisms, but also a consequence of an immunoregulatory imbalance. Alterations of homeostatic mechanisms might explain an imbalance of osteoclast activity leading to osteopenia.

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Interleukin 6 −174(G>C) gene polymorphism is related to celiac disease and autoimmune thyroiditis coincidence in diabetes type 1 children

Abstract

Introduction

Section snippets

Subjects and methods

IL-6 genotypes in diabetic children

Discussion

Conflicts of Interest

Lancet

Bone

Autoimmun. Rev.

Allergol. Immunopathol.

Enterovirus antibody levels during the first two years of life in prediabetic autoantibody-positive children

Diabetologia

Association between interleukin-6 polymorphism and age-at-onset of type 1 diabetes. Epistatic influences of the tumor necrosis factor-alpha and interleukin-1beta polymorphisms

Eur. Cytokine Netw.

Inflammatory markers and IL-6 polymorphism in peripheral arterial disease with and without diabetes mellitus

Vasc. Med.

The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis

J. Clin. Invest.

Is the association between TNF-alpha-308A allele and DMT1 independent of HLA-DRB1, DQB1 alleles?

Mediators Inflamm.

Polymorphism of the TNF-alpha gene and risk of celiac disease in T1DM children