Clock gene PERIOD3 polymorphism is associated with susceptibility to Graves’ disease but not to Hashimoto’s thyroiditis

ABSTRACT

Circadian disruption has been linked with immune-related morbidities including autoimmune diseases. PERIOD3 (PER3) clock gene is a key player in the mammalian circadian system. This study evaluated the possible association of PER3 rs2797685 (G/A) polymorphism and susceptibility of autoimmune thyroid diseases (AITD) and assessed if this SNP contributes to disease characteristics and serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The PER3 rs2797685 (G/A) polymorphism was assessed in 125 patients with AITD [Graves’ disease (GD), 69; Hashimoto’s thyroiditis (HT), 56] and 115 unrelated healthy controls. Subjects carrying at least one variant allele of PER3 rs2797685 (GA+AA) had increased risk for GD (OR 1.9, 95% CI 1–3.61, p= .05). There were no differences in the frequencies of genotypes and alleles of the PER3 rs2797685 polymorphism between HT patients and control subjects. No association was observed between genotypes of the studied SNP and any of the disease characteristics in GD and HT patients. The GA+AA genotype of PER3 rs2797685 was associated with lower levels of IL-6 in patients with Graves’ disease. There were no differences between genotypes of the studied SNP regarding TNF-α levels in GD, HT or control groups. In conclusion, this study provides the first evidence for a genetic association between GD and the PER3 gene, highlighting the possible relevance of polymorphisms in clock genes in the etiopathogenesis of AITD. However, functional studies to identify the underlying molecular mechanisms of this association are needed to translate these findings to clinical applications.     

甲状腺相关性眼病的研究及治疗进展

甲状腺相关性眼病(TAO)是具有一系列体征和症状的多因素自身免疫性疾病。糖胺聚糖(GAG)的过量沉积、炎性浸润以及细胞因子的过度产生是甲状腺相关性眼病的主要特征。甲状腺相关性眼病的临床表现多种多样,可以从轻度的眼睑肿胀、上睑退缩、结膜充血、眼球突出乃至重度的威胁视力的暴露性角膜溃疡和压迫性视神经病变。通常,根据病史和查体是可以直接诊断甲状腺相关性眼病。实验室检查和影像学检查对于诊断甲状腺相关性眼病也具有一定的作用。目前可以根据"NO SPECS"法、临床活动评分(CAS)和VISA分类这三种方法对TAO病情情况进行分类。甲状腺相关性眼部的治疗包括保守治疗、药物治疗、眼眶放射治疗和手术治疗等,需根据患者的病情来决定其治疗方案。本文的目的是帮助眼科医生了解甲状腺相关性眼病的分期(轻度,中度至重度和视力威胁)的重要性和相关的可用治疗方式。     

Graves眼病合并真菌性角膜感染1例

报道1例应用大剂量糖皮质激素治疗Graves眼病后导致的真菌性角膜感染。一位31岁的甲状腺机能亢进同时伴有双眼突出的女性,视力下降、眼睑浮肿。首先应用抗甲状腺药物(甲巯咪唑),1个月后,突眼症状无改善,遂给予大剂量甲强龙冲击和曲安奈德球后注射以减轻症状。3个月后,该患者出现角膜溃疡,双眼无光感。1周后体温升高,最高达39.5℃,给予抗菌治疗后体温仍波动在36.7～37.3℃之间。角膜溃疡分泌物涂片可见真菌芽孢和菌丝,予甲亢、抗真菌和营养支持治疗。1个月后,患者双眼睑浮肿减轻、角膜溃疡面积减少,视力恢复到可有光感,体温降至正常。     

Biologic activity of anti-thyrotropin anti-idiotypic antibody

We raised an antihuman thyrotropin anti-idiotypic antibody and showed that it was active at the thyrotropin receptor. Thus this antibody inhibited ¹²⁵I b-TSH binding to thyroid plasma membranes, stimulated adenylate cyclase activity through a guanyl nucleotide-dependent mechanism, increased radioiodide entry rate into isolated porcine thyroid follicular cells, and induced such cultured cells to organize into follicles. All these parameters are typical of thyrotropin action. This work raises the possibility that thyroid stimulating antibodies that cause the hyperthyroidism of Graves disease may be, at least in some patients, anti-thyrotropin anti-idiotypic antibodies. It also offers a novel method whereby antireceptor antibodies used in the isolation and characterization of the receptor may be raised from ligands.     

肿瘤坏死因子α基因启动子区多态性与皖南地区Graves病发生的关系

目的 探讨肿瘤坏死因子α（TNF-α）基因启动子区-238G/A和-308G/A多态与皖南地区汉族人Graves病（GD）发生的关系.方法 采用Taqman探针等位基因鉴别技术,检测和分析432例Graves病患者和629例正常对照者的TNF-α基因-238G/A和-308G/A多态位点的基因型和等位基因的频率.结果 TNF-α-238G/A和-308G/A多态基因型和等位基因频率在病例组和对照组的分布均无统计学差异（P＞0.05）,根据基因型分组进行临床病理特征比较亦未发现相关性.结论 TNF-α-238G/A和-308G/A多态与皖南地区汉族人GD发病无相关性.     

131I Radioiodine therapy in Graves’ disease: Us et coutumes,controversies and guidelines

For almost 80 years ¹³¹I radioiodine (RAI) therapy has proven to be an efficient and well-tolerated therapeutic option in patients with Graves’ disease (GD). Along with anti-thyroid drugs (ATD) and thyroidectomy, RAI is one the three major therapeutic tools for this autoimmune disease. The objective of this article is to review how RAI treatment is usually conducted in clinical routine and to discuss the main controversies surrounding this treatment in the light of recent national or international guidelines. This will be an opportunity to discuss the indications and contraindications for this treatment, its advantages and limits, and more generally its practical organization by a specialized team.     

Grave's disease affecting one thyroid lobe: About 2 cases

Graves’ disease is an autoimmune disorder of thyroid which is characterized by hyperthyroidism, diffuse goiter, ophthalmopathy. Due to the pathophysiological mechanism of the disease, the disease affects both thyroid lobes. Unilateral involvement of the thyroid gland in patients with Graves’ disease is a rare entity, which suggests a difference between the two thyroid lobes. Clarifying this phenomenon could be a line of research for a better understanding of the pathophysiology of Graves's disease. This entity must be known to the clinician in order to take it better and avoid misdiagnosis. Here we present two cases of Graves’ disease which had unilateral involvement of the thyroid gland and discuss the hypotheses explaining this observation.     

Association of PARP-1, NF-κB,NF-κBIA and IL-6, IL-1β and TNF-α with Graves Disease and Graves Ophthalmopathy

Background

Graves Disease (GD) is an autoimmune disorder affected by an interaction of multiple genes such as Nuclear Factor-κB (NF-κB), Nuclear Factor-κB Inhibitor (NF-κBIA), Poly (ADP-ribose) polymerase-1 (PARP-1) and cytokines like Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) and mostly accompanied by an ocular disorder, Graves Ophthalmopathy (GO). We hypothesize that there is a relationship between GD, GO, polymorphisms of inflammatory related genes and their association with cytokines, which may play important roles in autoimmune and inflammatory processes.

Subjects and methods

To confirm our hypothesis, we studied the polymorphisms and cytokine levels of 120 patients with GD and GO using PCR-RFLP and ELISA methods, respectively.

Results

We found that patients with GG genotype and carriers of G allele of PARP-1 G1672A polymorphism are at risk in the group having GD (p = 0.0007) while having GA genotype may be protective against the disease. PARP-1 C410T polymorphism was found to be associated with GO by increasing the risk by 1.7 times (p = 0.004). Another risk factor for development of GO was the polymorphism of del/ins of NFkB1 gene (p = 0.032) that increases the risk by 39%. Levels of cytokines were also elevated in patients with GD, but no association was found between levels of cytokines and the development of GO as there was no change in levels of cytokines.

Conclusions

We suggest that, PARP-1 and NFkB1 gene polymorphisms may be risk factors for developing Graves Disease and Ophthalmopathy.     

Radiotherapy in the treatment of Graves ophthalmopathy—to do it or not?

To the objective of this study is to evaluate the role and toxicity of radiotherapy in the treatment of Graves ophthalmopathy. In the years 2000–2003, 121 patients with malignant exophthalmos were treated with radiotherapy of the retrobulbar area to the total dose of 20 Gy in ten fractions with a 6 MeV photon beam. The treatment was performed by the team of the Clinic of Oncology of the Jagiellonian University Medical College in Cracow. The radiotherapy was preceded by intravenous steroid therapy: methylprednisolone acetate administered at the dose of 2 g/week for four consecutive weeks. The highest efficacy, expressed as improvement of all ocular symptoms, was observed for the combined treatment. Female and non-diabetic patients responded positively to the combined treatment. Radiotherapy combined with steroid therapy in the treatment of Graves ophthalmopathy seems to be an effective treatment for strictly defined indications. In the treatment of Graves–Basedow disease, radiotherapy is a well-tolerated treatment modality. Diabetes is a factor that worsens prognosis in Graves ophthalmopathy and female sex is a favourable factor for this condition.     

Interaction between gene A-positive Helicobacter pylori and human leukocyte antigen II alleles increase the risk of Graves disease in Chinese Han population: An association study

Objective

The current study explored the correlation of Helicobacter pylori and the polymorphisms of human leukocyte antigen II (HLA-II) alleles with Graves disease (GD).

Methods

A total of 216 patients with GD were recruited. 102 healthy volunteers constituted the control group. Levels of H. pylori immunoglobulin G (IgG) antibodies and H. pylori cytotoxin-associated gene A (CagA) IgG antibodies were detected using enzyme-linked immunosorbent assays. Molecular typing of the HLA-II alleles was conducted using polymerase chain reaction with sequence specific primers.

Results

H. pylori, particularly CagA-positive strains, HLA-DQA1*0201, and HLA-DQA1*0501 were associated with GD (P = 0.015, OR = 1.811; P = 0.000, OR = 3.085; P = 0.000, OR = 0.315; and P = 0.004, OR = 2.844, respectively). Patients with CagA-positive H. pylori and negative HLA-DQA1*0201 or positive HLA-DQA1*0501 were more likely exposed to GD compared with those with only one of these indices.

Conclusion

CagA-positive H. pylori, negative HLA-DQA1*0201, or positive HLA-DQA1*0501 may increase the risk of GD.