TNF gene polymorphisms in Graves' disease: TNF-308 A/G meta-analysis

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto thyroiditis, are associated with human MHC polymorphisms. The present study analysed two polymorphisms within tumour necrosis factor (TNF) genes (TNF-308 A/G SNP and TNFb (CT)n microsatellite) in a sample of 106 GD patients and 199 controls from the Tunisian population. The present study was designed to investigate genetic association of these polymorphisms (taken separately or considered as a haplotype) with GD development. Statistical analysis confirmed the association between the TNF-308 A allele and GD (p = 0.002), previously reported in a Tunisian familial study. The data from the present study suggest that the TNF-308 A allele plays a role in GD pathogenesis in the Tunisian population. This association was further confirmed by a meta-analysis on eight published studies (p < 0.0001). Haplotype analysis with GD revealed an associated haplotype (TNFb3-TNF-308 G haplotype: chi2 = 13.16; p = 0.0003).     

Association analysis of HLA-class II and class III gene polymorphisms in the susceptibility to mediterranean visceral leishmaniasis

HLA-DRB1, -DQB1, TNFalpha, TNFbeta, HSP70-2 and HSP70-hom genetic polymorphisms were analyzed in 156 unrelated patients who developed mediterranean visceral leishmaniasis (MVL) due to Leishmania infantum, and 154 unrelated healthy controls, who have got asymptomatic infection with this parasite and were selected on the basis of a positive leishmanin skin test (LST). A significantly reduced frequency of HLA-DR2 was observed among MVL patients (16.1%), compared with controls (26.3%) (relative risk = 0.54; p = 0.04). HLA-DR2/DR13 as well as HLA-DQB1*0201/- genotype frequencies were significantly lower in patients vs controls (relapse rate = 0.17 and 0.46, respectively; p < 0.05). However, using Bonferroni correction, none of these associations remained significant. No association was found, between either the -308 base pair TNFalpha gene polymorphism or the NcoI polymorphism in the first intron of the TNFbeta gene and susceptibility to MVL. Analysis of PstI and NcoI polymorphisms in the coding region of HSP70-2 and HSP70-hom genes, respectively, revealed a significantly higher frequency of homozygotes for the HSP70-2/PstI negative allele, among patients (21.8%) vs controls (12.6%) (relapse rate = 1.94; p = 0.04). Again, this result was not significant after using Bonferroni correction. These results do not support association between susceptibility to MVL and the MHC class II and class III loci analyzed in this study.     

Tumour necrosis factor haplotypes and asthma

Airway inflammation is a prominent feature of asthma. The pro- inflammatory cytokine Tumour Necrosis Factor shows constitutional variation in its level of secretion, which is linked to polymorphisms within the TNF gene complex and the surrounding MHC. In this study, 413 subjects in 88 nuclear families from a general population sample were examined for association with asthma and TNF polymorphisms. Ninety-two subjects were asthmatic, as defined by questionnaire. Asthma was significantly more common in subjects with allele 1 of the LT alpha NcoI polymorphism (LT alpha NcoI*1) (p = 0.005), and allele 2 of the TNF-308 polymorphism (TNF-308*2) (p = 0.004). The association was confined to the LT alpha NcoI*1/TNF-308*2 haplotype, so that it was not possible to differentiate between the effects of LT alpha NcoI and TNF- 308 alleles. The HLA-DR locus was excluded as a cause of this association. The results suggest that genetic influences on inflammation may be important in the pathogenesis of asthma.      

Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism

Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility.     

Association studies of the IL-23R gene in autoimmune thyroid disease in the Japanese population

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by interplays of genetic factors and environmental triggers. Interleukin-23 and its receptor (IL-23R) guide T cells towards the Th17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis, and Graves' ophthalmopathy (GO) in Caucasians. To determine whether variants in the IL-23R gene are associated with AITDs in Japanese, 464 Japanese AITD patients (290 with GD, 174 with HT) and 179 matched Japanese control subjects were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using TaqMan allelic discrimination assays and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. Case-control association studies were performed using the χ² and Fisher's exact tests with Yates correction. Of the four SNPs rs11209026 was non-polymorphic in our dataset. The other three SNPs were not associated with GD or GO or HT in our Japanese population. These results suggest that the IL-23R gene is associated with AITDs only in a specific ethnic group.     

Association of Interleukin-1B and Interleukin-4 Gene Variants with Autoimmune Thyroid Diseases in Tunisian Population

Autoimmune thyroid diseases (AITD) including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are complex genetic diseases. Cytokines IL-1B and IL-4 play a role in the pathogenesis of AITD. This study was conducted on Tunisian patients with GD or HT to investigate the association of IL-1B and IL-4 gene polymorphisms with the risk and the prognosis of AITD. A total of 358 healthy controls and 341 patients with AITDs (249 HT and 92 GD) were genotyped for IL-1B+3953C/T and IL-4 intron 3 VNTR polymorphisms. A significant association was found between IL-1B+3953C/T polymorphism and GD or HT, both in the dominant and additive models. The IL-1B+3953T allele was associated with GD (p = 0.0003, OR = 1.93, CI = 1.34-2.78) and HT (p = 0.009, OR = 1.43, CI = 1.09-1.88). The IL-4 VNTR polymorphism was associated only with HT risk both in additive (p = 0.03, OR = 0.31, CI = 0.11-0.86) and recessive (p = 0.03, OR = 3.04, CI = 1.13-8.17) models. No significant association was found between IL-1B+3953C/T polymorphism and change in the serum concentrations of TSH and FT4 in GD and HT patients. In HT patients, the IL-1B+3953T allele (p = 0.009, OR = 0.42, CI = 0.22-0.83) and the IL-1B+3953T/T genotype (p = 0.03, OR = 0.21, CI = 0.04-1.07) were more frequent in the absence than in the presence of an anti-TPO antibody. The proportion of HT patients with the P1P2 genotype of the IL-4 gene was significantly higher in the absence than in the presence of the anti-TPO antibody (p = 0.04, OR = 0.39, CI = 0.17-0.89). These preliminary results suggest that IL-1B and IL-4 gene polymorphisms may be associated with GD and HT susceptibility and may represent prognostic factors for predicting the severity of HT.     

Apolipoprotein E gene polymorphism is not a strong risk factor for diabetic nephropathy and retinopathy in Type I diabetes: case-control study

Background  

The autoimmune thyroid diseases (AITDs), such as Graves' disease (GD) and Hashimoto's thyroiditis (HT), appear to develop as a result of complex interactions between predisposing genes and environmental triggers. Susceptibility to AITDs is conferred by genes in the human leukocyte antigen (HLA) and genes unlinked to HLA, including the CTLA-4 gene. Recently, estrogen receptor (ER) β, located at human chromosome 14q23-24.1, was identifed. We analyzed a dinucleotide (CA)n repeat polymorphism located in the flanking region of ERβ gene in patients with AITDs and in normal subjects. High heterozygosity makes this polymorphism a useful marker in the genetic study of disorders affecting female endocrine systems. We also correlated a ERβ gene microsatellite polymorphism with bone mineral density (BMD) in the distal radius and biochemical markers of bone turnover in patients with GD in remission.     

Tumor necrosis factor-alpha -308 promoter polymorphism contributes independently to HLA alleles in the severity of rheumatoid arthritis in Mexicans

The aim of this study was to determine the frequency and potential relevance of the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha) in the severity of rheumatoid arthritis (RA) in Mexicans. HLA-DR and polymorphisms at positions -238 and -308 of TNF-alpha gene were determined in 137 Mexican RA patients (44 with severe and 93 with non-severe RA) as well as in 169 healthy controls (99 were typed for HLA-DR). We observed an increased frequency of HLA-DR4 in severe RA compared to healthy controls (pC=0.02, OR=2.33). TNF polymorphism analysis showed a significant increased frequency of TNF -238 GG genotype in the whole group of RA patients when compared to healthy controls (pC=0.007, OR=4.71). When the analyses were carried out separately in severe and non-severe RA patients, the increased frequency of -238 GG genotype only was observed in patients with non-severe forms of the disease. Analysis of -308 polymorphism showed increased frequency of -308 T2 (A) allele in severe RA when compared to non-severe disease (pC=0.011, OR=3.29) and to healthy controls (pC=0.002, OR=3.97). The data demonstrate that -308 T2 (A) allele is associated with susceptibility to develop severe RA in Mexicans. This association could be independent from HLA-DR alleles and might be used as a prognostic marker for severe RA.     

自身免疫性甲状腺病CTLA—4基因外显子1A／G^49多态性研究

目的　探讨细胞毒性T淋巴细胞相关抗原4（CTLA-4）基因外显子1的49位点A／G多态性与自身免疫性甲状腺病（AITDs）的相关性。方法　采用多聚酶链反应限制性片段长度多态性（PCR-RFLP）技术分析122例自身免疫甲状腺病患者,其中Graves’病（GD）87例,桥本甲状腺炎（HT）35例,84例健康对照的CTLA-4基因外显子1的49位点基因型。采用ELISA技术检测AITDs患者甲状腺功能,间接免疫荧光法检测甲状腺球蛋白抗体（TGAb）和甲状腺抗过氧化物酶抗体（TPOAb）。结果　AITDs患者CTLA-4／G     

Association between − 308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma

BACKGROUND: Tumour necrosis factor (TNF) is a pivotal cytokine in the inflammation underlying asthma. The TNF gene is located in the polymorphic HLA class 3 region on chromosome 6p. Several polymorphisms in this region have been described and associated with alteration of TNF secretion in vitro. OBJECTIVE: In this study we tested the hypothesis that two such polymorphisms, lymphotoxin alpha NcoI B*1 and -308 TNF2 may be components of the genetic predisposition to asthma. METHODS: Five hundred and fifty-six random individuals were studied, comprising approximately equal numbers of asthmatic subjects, with or without atopy, and a nonatopic nonasthmatic control group. In addition, 355 subjects (172 asthmatics) from 60 multiplex families were typed at the LTalpha NcoI locus. RESULTS: There was an association between allele two of the -308 TNF polymorphism and bronchial hyperreactivity (OR 2.12, 95% CI 1.04-4.32, P = 0.036). However, there was no association with LTalpha NcoI alleles. To determine whether this was influenced by linkage disequilibrium within the MHC, 91 subjects with bronchial hyperreactivity and 85 control subjects were typed for class 2 and 3 alleles. Following identification of the extended TNF2 haplotype, we found no independent association of these alleles with BHR. CONCLUSIONS: We conclude that the -308 TNF2 promoter polymorphism may form a component of the genetic predisposition to BHR in asthma.     

Evidence of association between FKBP1B and thyroid autoimmune disorders in a large Tunisian family

FKBP1B belongs to immunophilins superfamily and functions as a cytosolic receptor protein of FK506. The role of FKBP1B in the immunosuppressive pathway of FK506 is well established. Previously, we reported a strong evidence of linkage between D2S171 microsatellite marker (located in vicinity of FKBP1B gene) and susceptibility to autoimmune thyroid diseases (AITDs). In this study, we report linkage disequilibrium between the dimorphism (C/T) in the 3' untranslated region (3' UTR) of FKBP1B gene and susceptibility to AITDs. DNAs were extracted from a large Tunisian family affected with Graves' disease (GD) and Hashimoto's thyroiditis (HT) and analysed by PCR-RFLP using DraIII restriction enzyme. Our results showed an excess of transmission of the allele C from heterozygous parents to affected offspring (transmission disequilibrium test (TDT) = 4.76; p = 0.012). This suggests a linkage disequilibrium of 3' UTR (C/T) SNP with AITDs. Moreover, The FBAT analysis gives a significant association with the C allele under the recessive model (chi2 = 5.50; p = 0.018). These results support the involvement of FKBP1B gene in the genetic susceptibility to the AITDs development in the studied family.     

Estrogen receptor alpha dinucleotide repeat polymorphism in Japanese patients with autoimmune thyroid diseases

Background  

The autoimmune thyroid diseases (AITDs), comprising Graves' disease (GD) and Hashimoto's thyroiditis (HT), appear to develop as a result of complex interactions between predisposing genes and environmental triggers. Susceptibility to AITDs is conferred by genes in the human leukocyte antigen (HLA) and genes unlinked to HLA, including the CTLA-4 gene. Recently, an association to some estrogen receptor (ER)α genotypes with breast cancer, hypertension, osteoporosis, generalized osteoarthritis, and some autoimmune diseases such as rheumatoid arthritis has been reported. We have analyzed a dinucleotide (TA)n repeat polymorphism lying upstream of the human ERα gene in patients with AITDs and in normal subjects.     

Role of Different CD40 Polymorphisms in Graves’ Disease and Hashimoto’s Thyroiditis

Genome-wide association studies have led to the discovery of several susceptibility genes related to autoimmune thyroid diseases (AITDs). However, controversial results have been reported regarding the role of single-nucleotide polymorphism (SNP) of CD40 in the disease susceptibility. The objective of this study was to identify the relationship of the polymorphisms of three sites of CD40 with the susceptibility to AITD in the Chinese population. We genotyped three polymorphisms of CD40: C/T ?1 SNP, 58038T site of the third exon and C64610G site of the ninth exon in 196 GD cases, 121 HT cases and 122 control subjects. The three putative polymorphism sites were amplified by PCR for sequencing and analysis. The genotype frequencies of CD40 ?1 C/C genotype and C allele were significantly higher in the GD group than those in normal control. For the C64610G polymorphism, the C/G genotype was significantly more frequent in HT group than in control group, and the G allele frequencies in the GD and HT group were both higher than those in control group. These results indicated that there exist different susceptibility loci for AITD within CD40, each contributing a different effect in the onset and development of AITDs.     

Association of tumor necrosis factor and human leukocyte antigen DRB1 alleles with Graves' ophthalmopathy

Tumor necrosis factor (TNF)-alpha plays a central role in the development of ophthalmopathy in patients with Graves' disease (GD). The aim of this study was to investigate the association of TNF promoter polymorphisms at positions -1031 (T-1031C), -863 (C-863A), -857 (C-857T), -308 (G-308A), and -238 (G-238A) with Graves' ophthalmopathy (GO). We studied the distribution of TNF and human leukocyte antigen (HLA) DRB1 alleles in 228 Polish white patients with GD, 106 of whom had ophthalmopathy (NOSPECS class > or = III) and 248 healthy subjects. TNF -308A and HLA-DRB1*03 alleles were significantly increased in patients with GD compared with healthy subjects. Stratification analysis revealed no independent association of -308A with GD when the DRB1*03 status was considered. Subdividing GD according to eye involvement revealed that the distribution of TNF promoter haplotypes differed significantly in patients with or without ophthalmopathy. The haplotype containing the -238A allele was absent in GO. The association of G-238A with GO was independent of DRB1 alleles. These results indicate that TNF G-308A is associated with susceptibility to GD (however, this association is not independent of HLA-DRB1*03) and that TNF G-238A is associated with the development of ophthalmopathy, suggesting that G-238A or a gene in linkage disequilibrium may be disease modifying in GD.     

Lack of association between the polymorphism at the heat-shock protein (HSP70-2) gene and systemic lupus erythematosus (SLE) in the Mexican mestizo population

Major histocompatibility complex (MHC) alleles have been recognized as genetic factors for developing systemic lupus erythematosus (SLE). In the present study we analyzed whether a heat-shock protein gene (HSP70-2) is involved in determining susceptibility to develop SLE in a Mexican Mestizo population. A HSP70-2 Pst I polymorphism was detected by a restriction fragment length polymorphism analysis of polymerase chain reaction (PCR-RFLP) in 107 SLE patients and 158 healthy controls. No statistically significant differences were observed in the HSP70-2 allele distribution between patients and healthy controls. HLA-DR analysis showed an increased frequency of HLA-DR3 allele in the patients group (P < 0.05, OR = 2.26, EF = 6.0%). On the other hand, when we analyzed HSP70-2 polymorphism in relation to HLA-DR3 allele, we could only detect an increased frequency of AB genotype in the DR3 negative patients (pC < 0.05, RR = 2.6, EF = 11.3%). Linkage disequilibrium was observed for three haplotypes: HLA-DR3-HSP70-2A (D = 0.03, D' = 0.67, P < 0.01); HLA-DR1-HSP70-2A (D = 0.03, D' = 0.86, P < 0.01) and HLA-DR8-HSP70-2B (D = 0.02, D' = 0.46, P = 0.02). Our data indicate that HSP70-2 gene polymorphism as opposed to the other ethnic groups does not appear to be relevant in SLE susceptibility in Mexican patients and that the distribution of the different alleles depend on the frequency of HLA alleles associated with them.     

Tumor necrosis factor gene polymorphisms in Tunisian patients with Behcet's disease

Behcet's disease (BD) is an inflammatory disorder that is mainly characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. Recent reports focused on the genetic factors of susceptibility to this disease and especially the TNF in view of the major role played by this proinflammatory cytokine in the lesional process of Behcet's disease. In this report, we investigated the possible association between Behcet's disease and the TNF-alpha gene promoter polymorphisms -1031T/C, -308A/G, and the TNF-beta polymorphism +252A/G in Tunisian population. We compared the distribution of these polymorphisms between 89 BD patients and 157 healthy controls using polymerase chain reaction restriction fragment length-polymorphism (PCR-RFLP) analysis. The frequency of the TNF-alpha -1031C allele was significantly higher in Behcet's patients than in healthy controls (p = 0.015; chi(2) = 5.84; OR = 1.65; 95% CI = 1.08-2.54), whereas the frequencies of the TNF-alpha -308G and the TNF-beta +252G alleles were similar in the two compared groups. These results suggest that the variability of the TNF-alpha -1031T/C polymorphism can be associated with the susceptibility to Behcet's disease in our study group. Therefore, the TNF molecule may have an important genetically and/or functionally implication in the pathogenesis of BD in the Tunisian population.     

Analysis of chosen polymorphisms rs2476601 a/G – PTPN22, rs1990760 C/T – IFIH1, rs179247 a/G – TSHR in pathogenesis of autoimmune thyroid diseases in children

Background: Autoimmune thyroid diseases are multifactorial diseases with a genetic susceptibility and environmental factors. A potential role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, the interferon-induced helicase domain 1 (IFIH1) gene, the thyroid-stimulating hormone receptor (TSHR) gene polymorphisms on autoimmune thyroid diseases (AITDs) in adults has been established unequivocally, but there is still lack of research articles including group of children.

Objective and hypotheses: To estimate the association of polymorphisms of PTPN22, IFIH1 and TSH-R genes with the pre-disposition to Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) in children.

Methods: The study was performed in 142 patients with GD, 57 with HT and 160 healthy volunteers. The three single-nucleotide polymorphisms (SNPs): rs2476601 – PTPN22, rs1990760 – IFIH1 and rs179247 – TSHR were genotyped by TaqMan SNP genotyping assay using the real-time PCR.

Results: Rs2476601 A alleles were more frequent in patients with GD in comparison to healthy subjects (p?=?.009 with odds ratio [OR]?=?2.13). Rs2476601 A alleles were more frequent in patients with HT in comparison to healthy subjects (p?=?.008, OR?=?2.48). Rs1990760 T alleles were more frequent in male patients with GD in comparison to healthy males (p?=?.003, OR?=?3.00). In case of HT patients, rs1990760 T alleles were also more frequent in males compared to healthy subjects (p?=?.086, OR =2.47). Rs179247 A alleles were more frequent in patients with GD in comparison to healthy subjects (p?=?0.039, OR?=?1.51).

Conclusions: Rs2476601 A/G, Rs1990760 C/T and Rs179247 A/G polymorphisms could contribute to the development of AITDs in children. The main risk factor for rs2476601 and rs179247 is allele A. In case of rs1990760, the main risk factor is allele T.     

山东沿海地区碘营养状况和HLA等位基因DQA1*0501、DQA1*0201对AITDs发病的影响

目的探讨山东沿海地区自身免疫性甲状腺病（AITDs）与HLA等位基因DQA1＊0501、DQA1＊0201及碘营养状况对AITDs发病的影响。方法HLA等位基因测定采用PCR-SSP技术,尿碘浓度测定采用砷铈催化分光光度法。结果①DQA1＊0501等位基因为AITDs易感基因（GD和HT的OR值=2．14、2．5）;而DQA1＊0201为女性AITDs保护基因（GD和HT的OR值=0．33、0．27）。②AITDs组尿碘浓度高于300μg／L患者分布频率均显著高于对照组（P〈0．05）,且DQA1＊0501（＋）发生AITDs的OR值为2．7,DQA1＊0201（＋）的OR值为0．42;AITDs组碘正常组DQA1＊0501（＋）OR值为5．12,DQA1＊0201（＋）的OR值为0．21。③logistic回归分析发现尿碘浓度对数、DQA1＊0501为AITDs的易感因素,DQA1＊0201为保护因素。结论HLA-DQA1＊0501等位基因与该地区AITDs的发病易感性相关,而DQA1＊0201与女性患者的保护性相关。碘和HLA等位基因DQA1＊0501、DQA1＊0201共同影响GD、HT的发病。