Polymorphisms of interleukin-21 and interleukin-21-receptor genes confer risk for autoimmune thyroid diseases.
ABSTRACT: BACKGROUND: The abnormality of interleukin-21 (IL-21)-IL-21-receptor (IL-21R) system has been found in many autoimmune diseases including autoimmune thyroid diseases (AITDs). In this study, we investigated whether polymorphisms of the IL-21 and IL-21R are associated with Graves' disease (GD) and Hashimoto's thyroiditis (HT), two major forms of AITDs, among a Chinese population. METHODS: Rs907715, rs4833837, rs2221903 and rs2055979 of the IL-21 gene and rs3093301 and rs2285452 of the IL-21R gene were explored in a case-control study including 405 GD, 228 HT patients and 242 controls. These genes were genotyped by the PCR and restriction fragment length polymorphism (RFLP) analysis and the MASS spectrometry method. RESULTS: For IL-21 gene, we identified and confirmed a higher prevalence of A alleles of rs2221903 (P?=?0.018, OR?=?1.50 95% CI?=?1.07-2.09) in GD patients. We also found a significant association between rs2221903 and HT (allele: P?=?0.009, OR?=?1.69 95% CI?=?1.13-2.51; genotype: recessive P?=?0.021, OR?=?11.72 95% CI?=?1.46-94.13). For the IL-21R gene, compared with controls, the genotype frequencies of rs3093301 and rs2285452 were significantly different in HT patients using dominant genetic model (P?=?0.023, OR?=?1.61 95% CI?=?1.07-2.42; P?=?0.031, OR?=?1.71 95% CI?=?1.05-2.80, respectively). Furthermore, the haplotype AA containing the major alleles of rs4833837 and rs2221903 was associated with increased susceptibility to GD with an OR of 1.50(95% CI =1.08-2.09, P?=?0.016), and to HT with an OR of 1.69(95% CI =1.14-2.52, P?=?0.009). CONCLUSION: Our results indicated that the SNPs of the IL-21 gene is associated with the development of GD. In addition, we found that individuals with the SNPs of the common IL-21 and IL-21R may have higher risk of HT.
Project description:INTRODUCTION:Interleukin-21 (IL-21) is a cytokine which plays a significant role in the pathogenesis and disease activity of rheumatoid arthritis (RA). Genetic polymorphisms in the IL-21 gene may alter the synthesis of IL-21. The aim of this study was to examine IL-21 and IL-21R polymorphisms in patients with RA. MATERIAL AND METHODS:We examined 422 patients with RA and 338 healthy controls. Single nucleotide polymorphisms (SNPs) within the IL-21 (rs6822844 G>T, rs6840978 C>T, rs2221903 T>C) and IL-21R (rs2285452 G>A) genes were genotyped using TaqMan genotyping assays. RESULTS:There were no statistically significant differences in the distribution of studied genotypes and alleles between RA patients and the control group. To examine whether IL-21 polymorphisms affect disease activity in RA patients, we compared the distribution of IL-21 genotypes between patients with DAS28 ? 2.5 (patients with remission of disease symptoms) and patients with DAS28 > 2.5 (patients with active RA). Among patients with DAS28 > 2.5, increased prevalence of rs2221903 CT and CC genotypes was observed (OR = 1.54; 95% CI: 1.04-2.28; p = 0.035). CONCLUSIONS:The results of this study suggest that IL-21 and IL-21R gene polymorphisms are not risk loci for RA susceptibility, whereas the IL-21 rs2221903 polymorphism is associated with disease activity.
Project description:The aim of this study was to evaluate the relationship between interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) polymorphisms and the response to peginterferon alfa (PEG-IFN ?) therapy in HBeAg-positive chronic hepatitis B (CHB) patients.A total of 143 HBeAg-positive CHB patients treated for 48 weeks with PEG-IFN ? and followed up for 24 weeks post-treatment were retrospectively evaluated. Genotypes analysis was performed for IL-21 polymorphisms rs907715, rs2221903, and IL-21R polymorphisms rs3093301 and rs2285452. Serum IL-21 levels were measured by enzyme-linked immunosorbent assay.The end of virological response (EVR) rate was 46.9% (67/143) at the end of treatment, the sustained virological response (SVR) rate was 43.4% (62/143) and the complete response (CR) rate was 32.1% (46/143) at 24 weeks post-treatment. Patients who carried IL-21 rs 2221903 genotype AA had a rather higher rate of EVR (response rate: 52.4%, odds ratio [OR] 0.42, 95% confidence interval [CI]: 0.19-0.91, P?=?.021), SVR (response rate: 47.6%, OR 0.43, 95% CI: 0.19-0.95, P?=?.028), and CR (response rate: 38.1%, OR 0.31, 95% CI: 0.12-0.79, P?=?.014) when compared to those had AG genotype. Meanwhile, IL-21rs 2221903 genotype AA was also independently associated with markedly reduced HBsAg levels (>1og10?IU/mL) after 24 weeks treatment and low HBsAg levels (<100?IU/mL) at the end of treatment. IL-21 rs907715 AG/GG genotype was independently associated with SVR (OR: 2.92, 95% CI: 0.98-8.6, P?=?.039; OR: 3.23, 95% CI: 1.0-10.4, P?=?.039). Patients with IL-21 rs907715 AG/GG genotype had higher serum IL-21 levels than those with rs907715 AA genotype (P?=?.021).IL-21 rs2221903 and rs907715 polymorphisms were significantly associated with the treatment response to PEG-IFN ? among Chinese HBeAg-positive CHB patients.
Project description:BACKGROUND:We investigated the relationship between hepatitis B virus (HBV)-related pathogenesis and single nucleotide polymorphisms (SNPs) in interleukin-21 (IL-21)-JAK-STAT signaling pathway genes. METHODS:We used the high-resolution melting (HRM) method to genotype five SNPs (IL-21 rs2221903, IL-21 rs4833837, IL-21 receptor (IL-21R) rs2285452, JAK3 rs3008, and STAT3 rs1053023) in 546 HBV-infected patients and 353 healthy Chinese subjects. The HBV-infected patients were further divided into subgroups based on the HBV-related pathologies: chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC), and HBV-related hepatocellular carcinoma (HCC). RESULTS:There were no significant differences in the genotype and allele distributions of the five SNPs between the HBV-infected patients and healthy subjects. The genotype and allele frequencies were similar in the two groups for IL-21 rs2221903 (A>G, P = 0.83 and 0.67), rs4833837 (A>G, P = 0.80 and 0.49), IL-21R rs2285452 (G>A, P = 0.25 and 0.68), STAT3 rs1053023 (A>G, P = 1.00 and 0.96), and JAK3 rs3008 (C>T, P = 0.32 and 0.54). However, patients with the IL-21R rs2285452 AA genotype were more susceptible to HBV-related HCC than those with the IL-21R rs2285452 GA/GG genotype (P = 0.03, OR = 3.27, 95% CI = 1.16-9.20). The serological marker model of "HBsAg+, HBeAg+, HBcAb+" was predominant among patients with HBV infection. However, there was no association between the genotype's distribution of the five SNPs and the serological marker models (P > 0.05). CONCLUSIONS:These findings demonstrate that the IL-21R rs2285452 AA genotype increases the risk of HBV-related HCC in Chinese patients.
Project description:AIM:To verify a possible association between overall H. pylori and CagA+ H. pylori infection and autoimmune thyroid diseases (AITDs). METHODS:Consecutive patients with AITDs admitted to one single centre of Endocrinology during one solar year were examined. The diagnoses were Hashimoto thyroiditis (HT) in 76, Graves' Disease (GD) in 39, and aspecific thyroiditis (AT) in 44 patients. Controls were 136 individuals without AITDs. Median values of fT3, fT4, anti-thyreoglobulin (Tg) antibodies, IL-1?, IL-6, and TNF-? in patients were compared with those in controls. H. pylori infection and CagA status were determined serologically. Structural homology of some thyroid proteins with H. pylori antigens was investigated. RESULTS:H. pylori infection prevalence was significantly increased in GD (66.6%) and HT (64.4%) patients, vs. 29.4% of controls and 34.0% of AT. CagA seropositivity was significantly more frequent in GD (46.1%) and HT (46.9%) infected patients, vs. infected controls (20%). fT3 and fT4 median values were significantly decreased in infected CagA+ GD patients vs. uninfected GD patients. IL-1? median values were increased in patients respect to controls, independently of the clinical form of AITD. Median values of IL-6, TNF-? and anti-Tg autoantibodies in CagA infected patients were significantly higher than those measured in infected CagA- and uninfected patients and in infected CagA+ controls. The examined thyroid proteins shared putative conserved domains with numerous bacterial antigens. CONCLUSIONS:Overall H. pylori and CagA+ H. pylori infection were associated with GD and HT, putatively through an increased inflammatory status and molecular mimicry.
Project description:BACKGROUND: Polymorphisms of the CC chemokine receptor 6 (CCR6) and RNASET2 tag SNP have been shown to be associated with the susceptibility to several immune-related diseases. This study was conducted to identify the association of CCR6 and RNASET2 tag SNP with autoimmune thyroid diseases (AITDs) in the Chinese Han population. METHODS: We enrolled 1061 patients with AITDs, including 701 patients with Graves' disease (GD) and 360 patients with Hashimoto's thyroiditis (HT), and 938 healthy individuals for a case-control genetic association study. Three CCR6 single nucleotides polymorphisms (SNPs) (rs3093023/rs3093024/rs6902119) and one tagging SNP (rs9355610) within RNASET2 gene were selected for genotyping by multiplex polymerase chain reaction (PCR) and ligase detection reaction (LDR). RESULTS: The frequency of rs9355610 genotypes in the patients with GD differed significantly from that in the controls (p = 0.017). The frequency of the minor G allele of rs9355610 was significantly higher in the GD patients than in the healthy controls (p = 0.005, OR = 1.225, 95% CI:1.063-1.412). However, we could not find significant differences in the genotype or allele frequencies of HT patients compared with healthy controls. After gender stratification, the frequency of the minor G allele in both male and female GD patients was significantly higher than that in the healthy controls (p = 0.036, OR = 1.308, 95% CI:1.017-1.684 ; p = 0.048, OR = 1.19, 95% CI:1.001-1.413; respectively);. Furthermore, the frequency of haplotype AT in GD patients was significantly lower than that in their control groups (p = 0.003) and showed a protective effect against GD (OR = 0.806, 95% CI: 0.699-0.929). The frequency of haplotype GT in GD patients was significantly higher than that in their control groups (p = 0.048), indicating that GT was the risk haplotype to GD (OR = 1.267, 95% CI: 1.001-1.603). There were no significant differences in the allele or genotype frequencies of three SNPs of CCR6 (rs3093023/rs3093024/ rs6902119) gene between GD patients, HT patients and controls. CONCLUSIONS: Our results suggest that the rs9355610 tag SNP of RNASET2 gene is positively associated with susceptibility to GD in the Chinese Han population. No association was found for the tested CCR6 SNPs.
Project description:The association of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene and susceptibility to autoimmune thyroid diseases (AITDs) has been studied extensively. However, the results were not the same in different ethnic groups. We updated the meta-analysis of association of CTLA-4 gene polymorphisms with AITDs and summarized the results in specific ethnicity. The associations of A49G gene polymorphism with GD, A49G gene polymorphism with HT, CT60 gene polymorphism with GD, and CT60 gene polymorphism with HT were summarized based on the literatures published up to October 30, 2014, in English or Chinese languages. The participants involved in the studies of A49G with GD, A49G with HT, CT60 with GD, and CT60HT were 39004 subjects (in 51 studies), 13102 subjects (in 22 studies), 31446 subjects (in 22 studies), and 6948 subjects (in 8 studies), respectively. The pooled ORs of CTLA-4 gene polymorphisms with AITDs were larger than 1.00, and the 95% CIs of ORs were statistically significant among whole population analyses. However, the subgroup analysis demonstrated that pooled ORs of A49G polymorphisms with GD among Africans or Americans are less than 1.00. The accumulated evidence suggests that the G allele mutant of A49G and CT60 increased the risks of HT and GD.
Project description:BACKGROUND:The single nucleotide polymorphisms of interleukin-21 (IL-21) gene were confirmed to be related to various diseases, but no studies have examined the possible role of IL-21 single nucleotide polymorphisms (SNPs) (rs907715, rs2221903, and rs12508721) in gastric precancerous lesions. AIM:To explore the associations between SNPs of IL-21 gene (rs907715, rs2221903, and rs12508721) and gastric precancerous lesions in a Chinese population. METHODS:Three SNPs of IL-21 were genotyped using polymerase chain reaction-ligase detection reaction in 588 cases and 290 healthy controls from May 2013 to December 2016 in northwestern China. Gastric precancerous lesions were confirmed by endoscopic examination and categorized as non-atrophic gastritis, atrophic gastritis, and intestinal metaplasia. Descriptive statistic and logistic regression were used for data analyses. RESULTS:IL-21 rs907715 genotype CC and C frequencies were higher in in patients with gastric precancerous lesions than in the controls (OR = 1.59, 95%CI: 1.06-2.38, P = 0.013; OR = 1.28, 95%CI: 1.01-2.22, P = 0.044, respectively) after adjusting for confounding factors. For SNP rs907715 in intestinal metaplasia patients, significant differences between cases and controls were observed in the frequencies of genotype CC and C (OR = 1.92, 95%CI: 1.24-2.98, P = 0.004; OR = 1.53, 95%CI: 1.04-2.24, P = 0.028, respectively); for non-atrophic gastritis and atrophic gastritis patients, the CC and C genotypes showed no significant association with risk in all models. No association between either rs2221903 or rs12508721 and gastric precancerous lesions was found in the present study. In the haplotype analysis, the TC haplotype (rs907715 and rs12508721) and TT haplotype (rs2221903 and rs907715) were more frequent in the case group than control group (P < 0.05). CONCLUSION:Our findings indicate that SNP rs907715 of IL-21 gene is associated with gastric precancerous lesions. The TC haplotype (rs907715 and rs12508721) and TT haplotype (rs2221903 and rs907715) increased the risk of gastric precancerous lesions. If confirmed, these findings will shed light on the etiology of precancerous lesions.
Project description:Background: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are autoimmune thyroid disorders (AITDs). These conditions have been associated to abnormalities in circulating regulatory T cells (Tregs). We postulated that immune perturbations could be more pronounced at the thyroid tissue level. Methods: The phenotype of PBMCs and immune cells infiltrating thyroid tissue from 19 patients with HT, 21 patients with GD, and 30 controls has been analyzed by flow cytometry. Results: We report that blood and thyroid Treg cell subsets are similarly represented in all AITDs patients and controls. Increased Lymphoid tissue inducer (LTi)-like ILC3 and CXCR5+ PD-1hi CD4+ T follicular helper cells (Tfh) tissue-infiltrating cells, together with the prevalence of tertiary lymphoid structures (TLS) and germinal centers (GCs) represented a typical immune signature in all HT and 60% of GD patients. In the remaining group of GD patients, the absence of the aforementioned abnormalities was associated with a higher prevalence of ophthalmopathy. Conclusion: Tissue infiltrating Lymphoid Tissue inducer-like group 3 Innate Lymphoid cells and T follicular helper cells are increased in most thyroid autoimmune disease.
Project description:The etiology of lung cancer is still incompletely understood. Previous studies have suggested the association between IL-21 polymorphisms and autoimmune diseases, however, little is known about its role in lung cancer susceptibility. Here, we investigated the role of two SNPs of IL-21 gene in a cohort of non-small cell lung cancer (NSCLC) patients. A total of 128 NSCLC patients and 156 healthy controls were genotyped. Multivariate logistic regression was used to analyze the association between IL-21 polymorphisms and NSCLC risk. Our data showed that both rs907715 and rs2221903 were significantly associated with lung cancer susceptibility, and patients carrying rs907715A (P = 0.007, adjusted OR = 0.60, 95% CI = 0.42-0.87) or rs2221903G (P = 0.020, adjusted OR = 0.52, 95% CI = 0.30-0.90) allele had a decreased risk of NSCLC. Further study identified that the association between IL-21 polymorphisms and NSCLC risk was limited to lung adenocarcinoma. Haplotype analysis revealed that the AG (P = 0.006, OR = 0.072 95% CI = 0.011-0.451) and AA (P = 0.022, OR = 0.657, 95% CI = 0.458-0.941) haplotypes of rs907715/rs2221903 were associated with a decreased risk of NSCLC, whereas the GA (P = 0.0001, OR = 1.932, 95% CI = 1.378-2.710) haplotype was associated with an increased risk. In conclusion, our study demonstrates the association between IL-21 polymorphisms (rs907715 and rs2221903) and NSCLC risk in a Chinese Han population, indicating their potential role in lung cancer detection and treatment.
Project description:To investigate the association of CLEC16A gene polymorphisms and autoimmune thyroid diseases (AITDs). Six hundred sixty seven Han Chinese patients with AITDs were selected as study subjects, including 417 patients with Graves' disease (GD), 250 patients with Hashimoto's thyroiditis (HT) and 301 healthy control patients. Polymerase chain reaction-restriction fragment length polymorphism (RFLP) and the mass spectrometry technique were used to genotype five CLEC16A single-nucleotide polymorphisms (SNPs) (rs12708716, rs12917716, rs12931878, rs2903692, and rs6498169). Higher frequency of G allele of rs6498169 CLEC16A gene in AITDs patients [P = 0.029, odds ratio (OR) 1.29 and 95% confidence interval 1.022-1.505] was observed. In addition an association between rs6498169 and HT was observed with statistical significance (P = 0.018, OR 1.335, 95% confidence interval 1.051-1.696). Furthermore, the GG haplotype containing the major allele of (rs12708716 and rs6498169) was associated with an increased risk of HT (P = 0.0148, OR 1.344). When patients with HT and controls were compared, results from the dominant and recessive models showed that the genotype frequency of rs6498169 were at borderline levels (P = 0.054 and P = 0.05), and the other four SNPs of CLEC16A gene showed no significant association with AITDs. Our results suggest that polymorphisms rs6498169 of CLEC16A gene confers susceptibility to AITDs. We therefore disclose for the first time the association of rs6498169 SNP with AITDs.