Thyroid Eye Disease: Pilot Study Comparison Between Patients in United States-Based and India-Based Practices.

PURPOSE: Thyroid eye disease (TED) phenotype varies by ethnicity/race and genetic/environmental factors. This study compared demographic and clinical characteristics of TED patients from the US and India. DESIGN: Observational pilot study . METHODS: Sixty-four patients with TED ages ≥18 years old with active disease (onset of symptoms ≤18 months or presenting clinical activity score (CAS) ≥4) were recruited between March and October 2021 from clinical practices in the United States (Philadelphia, PA) (n = 30) and India (Hyderabad, India) (n = 34). Data collection at baseline and 3 months included clinical measurements, thyroid disease history, and photographs. Ocular symptoms and quality of life data were obtained by phone interview. CAS was calculated using the standard 7-point scale. RESULTS: There was no statistically significant difference in age, TED duration, or smoking status between patient groups. Both groups had good vision, a low rate of optic neuropathy, and comparable exophthalmometry. US patients were predominantly female (86.7% [26/30]), with a history of hyperthyroidism (96% 29/30). In comparison, Indian patients were 52.9% (18/34, P = .004) female; underlying thyroid disease was distributed between hyperthyroidism (52%), hypothyroidism (17.6%) and euthyroid (9.7%). Mean (SD) CAS in the US cohort was double the score in the India cohort (4.2 (1.7) vs 1.65 (1.7), respectively) (P < .0001). However, patients at both sites experienced subjective symptoms of TED at a similar frequency. CONCLUSIONS: Observed differences in TED between US and Indian patients warrant further investigation to elucidate differences in pathogenesis, disease expression, or other factors that may influence TED in diverse populations.

The VDR gene confers a genetic predisposition to Graves' disease and Graves' ophthalmopathy in the Southwest Chinese Han population.

OBJECTIVE: Graves' disease (GD) is a common autoimmune disease manifesting with diffuse symmetric thyroid gland enlargement, pretibial myxedema, and Graves' ophthalmopathy (GO). Recently, the vitamin D receptor (VDR) gene has been linked to various autoimmune diseases. This study aimed to investigate the association of VDR gene polymorphisms with susceptibility to GD and GO in the Southwest Chinese Han population. METHODS: A two-stage association study was performed in 1,209 controls and 650 GD patients by PCR-RFLP assay. Real-time PCR and ELISA were carried out to quantify gene expression and cytokine production. RESULTS: The first-stage study showed that the frequency of VDR/Apa I AA genotype was significantly increased in GD (Pc = 1.67 × 10-2, OR = 1.98). The second-stage and combined studies confirmed the association of VDR/Apa I with GD (AA genotype: Pc = 3.45 × 10-4, OR = 1.87; A allele: Pc = 2.62 × 10-2, OR = 1.20). The stratification analysis showed that GO patients had a higher frequency of the VDR/Apa I AA genotype (Pc = 8.69 × 10-5, OR = 2.84). Functional experiments showed a decreased VDR expression and TGF-ß1 production as well as an increased IL-17 production in VDR/Apa I AA genotype carriers. CONCLUSION: The VDR/Apa I polymorphism is significantly associated with GD and GO, and it may be involved in the development of GD and GO by influencing VDR mRNA expression levels and the secretion levels of cytokines.

Thyroid eye disease in New Zealand: interaction between ethnicity and smoking status.

AIM: This study was conducted to describe the epidemiology of thyroid eye disease (TED) in New Zealand. METHODS: One hundred and sixty-one subjects with TED seen over a 14-year period in Auckland, from a combined ophthalmology-endocrinology clinic, had data extracted from clinical notes. RESULTS: Median age at onset was 47.0±15.1 years and 77.6% were female. Crude yearly incidence of TED (per 1,000,000) was 12.6 in non-smokers and 67.3 in smokers (p<0.001).  On univariate analysis, female gender, Maori ethnicity and smoking were associated with incidence of TED. On multivariate analysis, female gender and smoking status were associated with risk of TED, and the difference in ethnicity was explained by smoking status. Maori subjects with TED were more likely to be current smokers (72.7%) compared to European (39.2%), Pacific Peoples (33.3%), Asian (8.3%) and Other (12.5%). Maori ethnicity and current smokers were associated with a higher clinical activity score at presentation (p=0.049 and p=0.027). CONCLUSION: A strong association was demonstrated with female gender and smoking status and rate of TED. Maori have increased rates of TED; however, this difference was explained by smoking. Eliminating smoking would result in at least a 28.1% reduction in TED incidence in New Zealand.

Interaction Between CCR6+ Th17 Cells and CD34+ Fibrocytes Promotes Inflammation: Implications in Graves' Orbitopathy in Chinese Population.

Purpose: Recent reports suggest that Th17 immunity and bone marrow-derived CD34+ fibrocytes contribute to the pathogenesis of Graves' orbitopathy (GO). This study investigated interactions between Th17 cells and fibrocytes in GO inflammation in Chinese subjects. Methods: Th17 cells and fibrocytes were derived from blood samples from Chinese GO patients and healthy controls. Proportions and phenotypes of Th17 cells, regulatory T cells (Tregs), and fibrocytes were examined by flow cytometry. Exogenous IL-17A was used to study inflammatory activity of fibrocytes from GO patients and control subjects. Coculture, quantitative RT-PCR, Luminex, and transwell assays were performed to investigate the relationship between Th17 cells and fibrocytes. Results: CC-chemokine receptor 6 (CCR6+) Th17 cells were increased in both active (P < 0.001) and inactive (P < 0.05) GO patients, compared with healthy controls. There was a positive correlation between number of CCR6+ Th17 cells and GO clinical activity score (P < 0.0001, r = 0.8176). Further, CD34+ fibrocytes were increased in GO patients, with increased expression of IL-17RA (P < 0.05), CD80 (P < 0.05), and CD86 (P < 0.05). A decreased population of effector Treg cells (P < 0.01) and increased CTLA-4 expression on naïve Treg cells (P < 0.05) were observed in GO patients. IL-17A stimulated cytokine production in fibrocytes; GO fibrocytes exhibited more robust production than normal fibrocytes. Autologous Th17 cells promoted inflammatory and antigen-presenting functions of GO fibrocytes; conversely, fibrocytes enhanced Th17 cell-function and recruited Th17 cells in a macrophage inflammatory protein 3 (MIP-3)/CCR6-dependent manner. Conclusions: The crosstalk between CCR6+ Th17 cells and fibrocytes plays a role in the pathogenesis of GO. Suppressing these interactions may be a candidate molecular target for therapeutic approaches of GO.

Identification and Functional Characterization of ST3GAL5 and ST8SIA1 Variants in Patients with Thyroid-Associated Ophthalmopathy.

PURPOSE: This study was conducted to identify and to functionally characterize genetic variants in ST3GAL5 and ST8SIA1 in Korean patients with thyroid-associated ophthalmopathy (TAO). MATERIALS AND METHODS: Genetic analyses were conducted using DNA samples from TAO patients (n=50) and healthy subjects (n=48) to identify TAO-specific genetic variants of ST3GAL5 or ST8SIA1. The effect of each genetic variant on the transcription or expression of these genes was examined. Additionally, correlations between functional haplotypes of ST3GAL5 or ST8SIA1 and clinical characteristics of the patients were investigated. RESULTS: Six promoter variants and one nonsynonymous variant of ST3GAL5 were identified, and four major promoter haplotypes were assembled. Additionally, three promoter variants and two major haplotypes of ST8SIA1 were identified. All ST3GAL5 and ST8SIA1 variants identified in TAO patients were also found in healthy controls. Promoter activity was significantly decreased in three promoter haplotypes of ST3GAL5 and increased in one promoter haplotype of ST8SIA1. Transcription factors activating protein-1, NKX3.1, and specificity protein 1 were revealed as having roles in transcriptional regulation of these haplotypes. The nonsynonymous variant of ST3GAL5, H104R, did not alter the expression of ST3GAL5. While no differences in clinical characteristics were detected in patients possessing the functional promoter haplotypes of ST3GAL5, exophthalmic values were significantly lower in patients with the ST8SIA1 haplotype, which showed a significant increase in promoter activity. CONCLUSION: These results from genotype-phenotype analysis might suggest a possible link between the ST8SIA1 functional promoter haplotype and the clinical severity of TAO. However, further studies with larger sample sizes are warranted.

Severe pediatric Graves orbitopathy in adolescents of African origin.

This article reports on two cases of severe pediatric Graves orbitopathy (GO) in two adolescents of African origin. Two black male adolescents presented with highly active GO and signs of beginning compressive optic neuropathy. Neither of them were smokers nor had a family history of GO. Besides urgent referral to pediatric endocrinologists, intravenous methylprednisolon pulse therapy was initiated. In spite of the fluctuating thyroid hormone levels in the initial phase of antithyroid therapy, intravenous steroid administration stopped the progression of malignant GO rapidly in both of our patients without any considerable side effects. Although the course of GO during childhood is considered to be mild, severe, sight threatening GO-requiring immunosuppression-may occur at young age, as in the reported adolescent patients of African descent.

Modified Full Thickness Graded Blepharotomy for Upper Eyelid Retraction Associated With Thyroid Eye Disease in East Asians.

PURPOSE: To evaluate the functional and cosmetic outcomes of modified full thickness graded blepharotomy when used for East Asian patients with upper eyelid retraction of thyroid eye disease (TED). METHOD: Medical records of each patient who underwent modified full-thickness blepharotomy at Korea University Guro Hospitals from January 2009 to February 2014 to correct upper eyelid retraction resulting from TED were retrospectively reviewed. RESULTS: Modified full-thickness graded blepharotomies were performed on 22 eyelids of 18 patients. The most common preoperative upper eyelid retraction-associated symptom was asymmetry of the upper eyelid (14 patients, 77.7%) followed by discomfort (10 patients, 55.5%), photophobia (5 patients, 27.7%), and epiphora (4 patients, 22.2%). Most preoperative symptoms improved after blepharotomy (Table 1). Preoperatively, upper eyelid retraction (MRD1; midpupil marginal reflex distance) ranged from 2.3 mm to 6.8 mm (mean, 5.23 ± 0.89) in 22 lids; postoperatively, lid retraction significantly decreased to 3.26 ± 1.23 mm (P = 0.03 by independent t test) (Table 2). Lid retraction was divided into 3 groups according to severity; a severe group (5 eyelids, 27.7%), a moderate group (14 eyelids, 63.6%), and a mild group (3 eyelids, 13.6%). The MRD1 improved regardless of severity (P = 0.03 in the severe group, P = 0.02 in the moderate group, and P = 0.04 in the mild group by independent t test). The MRD1 improvement did not differ significantly among groups (P = 0.08 by Pearson χ t test). At 6 months postoperatively, the midpupil marginal reflex distance was the perfect height in 13 of 22 lids (59.0%), with a mean reduction of 3 mm, whereas 7 of 22 eyelids (31.8%) were at acceptable height and 2 eyelids (9.0%) showed failure. Overall, 18 eyelids (90.9%) exhibited objectively satisfactory results (perfect or acceptable) at 6 months after surgery (Table 3). CONCLUSIONS: Modified graded full thickness eyelid blepharotomy is a reliable and safe method for upper eyelid lengthening for East Asian patients with upper eyelid retraction of TED that offers excellent functional and cosmetic results.

Biometric and refractive changes after orbital decompression in Korean patients with thyroid-associated orbitopathy.

PURPOSE: To determine the biometric and refractive changes after orbital decompression in Korean patients with thyroid-associated orbitopathy (TAO). METHODS: Retrospective, observational study (between October 2012 and September 2014) was performed. Patients with TAO undergoing orbital decompression for stable proptosis received ophthalmic examinations, including Hertel exophthalmometry, A-scan biometry, autorefraction measures, corneal topography, and wavefront aberration measures, before orbital decompression and again 2 months after surgery. RESULTS: Included in the study were 43 eyes from 23 patients. The mean exophthalmometric value decreased by 4.1 mm 2 months after orbital decompression (P<0.001). On average, axial length (AL) increased significantly by 0.08 mm (P<0.001); specifically, 37 (86%) of the 43 eyes had increased AL. Whereas anterior chamber depth and lens thickness showed no significant changes (P=0.086 and P=0.905, respectively), the mean spherical refraction and spherical equivalent (SE) decreased by 0.35 and 0.48 D, respectively (P=0.008 and P<0.001, respectively). However, cylindrical refraction and axis showed no significant changes (P=0.057 and P=0.218, respectively). The changes in AL and SE were significantly correlated (R=-0.411, P=0.009). Notably, there were no changes in corneal topography or wavefront aberration after orbital decompression. CONCLUSIONS: TAO patients who underwent orbital decompression showed myopic refractive change via increase in AL. Possible refractive changes should be considered in cases of TAO complaining of decreased visual acuity after orbital decompression.

Lack of association between polymorphisms in the UBASH3A gene and autoimmune thyroid disease: a case control study.

OBJECTIVE: The aim of this study was to investigate UBASH3A gene variation association with autoimmune thyroid disease and clinical features in a Chinese Han population. SUBJECTS AND METHODS: A total of 667 AITD patients (417 GD and 250 HT) and 301 healthy controls were genotyped for two single nucleotide polymorphisms (SNPs) rs11203203, rs3788013 of UBASH3A gene, utilizing the Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform. RESULTS: Between the control group and AITD, GD and HT group, no statistically significant difference was observed in the genotypic and allelic frequencies of the two SNPs. There was no significant difference in allelic frequencies of the two SNPs between GD with and without ophthalmopathy. There was no significant difference in haplotype distributions between the control group and AITD, GD or HT group. CONCLUSION: Rs11203203 and rs3788013 in UBASH3A gene may not be associated with AITD patients in Chinese Han population.

Lack of association between polymorphisms in the UBASH3A gene and autoimmune thyroid disease: a case control study / Falta de associação entre polimorfismos do gene UBASH3A e doença tiroidiana autoimune: estudo caso controle

Objective: The aim of this study was to investigate UBASH3A gene variation association with autoimmune thyroid disease and clinical features in a Chinese Han population. Subjects and methods: A total of 667 AITD patients (417 GD and 250 HT) and 301 healthy controls were genotyped for two single nucleotide polymorphisms (SNPs) rs11203203, rs3788013 of UBASH3A gene, utilizing the Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform. Results: Between the control group and AITD, GD and HT group, no statistically significant difference was observed in the genotypic and allelic frequencies of the two SNPs. There was no significant difference in allelic frequencies of the two SNPs between GD with and without ophthalmopathy. There was no significant difference in haplotype distributions between the control group and AITD, GD or HT group. Conclusion: Rs11203203 and rs3788013 in UBASH3A gene may not be associated with AITD patients in Chinese Han population. .

Objetivo: O objetivo deste estudo foi investigar a variação no gene UBASH3A com a doença tiroidiana autoimune e características clínicas na população chinesa Han. Sujeitos e métodos: Um total de 667 pacientes com DTAI (417 com DG e 250 com TH) e 301 controles saudáveis foi genotipado para dois polimorfismos de nucleotídeo simples (SNPs) rs11203203, rs3788013 do gene UBASH3A, usando-se a plataforma MALDI-TOF-MS (Ionização/Dessorção de Matriz Assistida por Laser – Tempo de Voo/Espectrômetro de Massa). Resultados: Não foram observadas diferenças significativas entre as frequências genotípicas e alélicas dos dois SNPs nos grupos controle e DTAI, DG e TH. Não houve diferenças significativas entre as frequências alélicas dos dois SNPs em pacientes com DG com ou sem olftalmopatia. Não houve diferenças significativas nas distribuições de haplótipos no grupo controle e nos grupos DTAI, DG e TH. Conclusão: Os SNPs rs11203203 e rs3788013 do gene UBASH3A podem não estar associados a pacientes com DTAI na população chinesa Han. .

Evaluation of thyroid eye disease: quality-of-life questionnaire (TED-QOL) in Korean patients.

OBJECTIVE: To assess impaired quality of life (QOL) of Korean patients with thyroid eye disease (TED) using the TED-QOL questionnaire, to evaluate the adaptability of the questionnaire, and to assess the correlation between TED-QOL and scales of disease severity. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Total of 90 consecutive adult patients with TED and Graves' disease were included in this study. METHODS: TED-QOL was translated into Korean and administered to the patients. The results were compared with clinical severity scores (clinical activity score, VISA (vision loss (optic neuropathy); inflammation; strabismus/motility; appearance/exposure) classification, modified NOSPECS (no signs or symptoms; only signs; soft tissue; proptosis; extraocular muscle; cornea; sight loss) score, Gorman diplopia scale, and European Group of Graves' Orbitopathy Classification). RESULTS: Clinical scores indicating inflammation and strabismus in patients with TED were positively correlated with overall and visual function-related QOL (Spearman coefficient 0.21-0.38, p < 0.05). Clinical scores associated with appearance were positively correlated with appearance-related QOL (Spearman coefficient 0.26-0.27, p < 0.05). In multivariate analysis, age, soft-tissue inflammation, motility disorder of modified NOSPECS, and motility disorder of VISA classification had positive correlation with overall and function-related QOL. Sex, soft-tissue inflammation, proptosis of modified NOSPECS, and appearance of VISA classification had correlation with appearance-related QOL. In addition, validity of TED-QOL was proved sufficient based on the outcomes of patient interviews and correlation between the subscales of TED-QOL. CONCLUSIONS: TED-QOL showed significant correlations with various objective clinical parameters of TED. TED-QOL was a simple and useful tool for rapid evaluation of QOL in daily outpatient clinics, which could be readily translated into different languages to be widely applicable to various populations.

Ethnic differences in the clinical presentation of Graves' ophthalmopathy.

Ethnic differences in a number of eye conditions have been described. The literature on ethnic differences in Graves' ophthalmopathy (GO) is limited. There is some evidence to suggest Asian patients with GO may manifest milder phenotypic features of GO, with less proptosis and evidence of extraocular muscle involvement and restriction. The reasons for these differences are likely to be multifactorial and include orbital and lid anatomy, genetic background and autoimmune responses including TSH -receptor antibodies. These differences should be kept in mind when evaluating and managing patients with GO.

Acquired lower eyelid epiblepharon in thyroid-associated ophthalmopathy of Koreans.

PURPOSE: To investigate the prevalence and clinical features of acquired lower eyelid epiblepharon in Korean patients with thyroid-associated ophthalmopathy (TAO) and compare the pathogenic features of acquired and congenital epiblepharon. DESIGN: Retrospective, nonrandomized, comparative case series, cross-sectional study. PARTICIPANTS: A total of 494 Korean patients with TAO and 845 Korean patients with congenital lower eyelid epiblepharon. METHODS: The medical records were reviewed, and the presence, location, and extent of epiblepharon were identified. Clinical features of TAO (lower eyelid retraction, exophthalmos, and elevation limitation) were compared between patients with TAO with and without epiblepharon. Acquired epiblepharon was classified into 3 types according to the location and extent. The prevalence of epiblepharon types was determined and evaluated for associations with TAO clinical features. Comparisons were made between the prevalence of epiblepharon types in acquired and congenital epiblepharon. MAIN OUTCOME MEASURES: Prevalence, location, and extent of epiblepharon; association with clinical features of TAO; and difference from congenital epiblepharon. RESULTS: An acquired lower eyelid epiblepharon was found in 42 (8.5%) of 494 patients with TAO. The mean age of patients with TAO with epiblepharon (34.2±13.5 years) was significantly lower than that of patients with TAO without epiblepharon (46.5±14.1 years) (P = 0.000). Lower eyelid retraction (0.78±1.11 mm) was more severe in patients with TAO with epiblepharon than in patients without epiblepharon (0.30±0.73 mm) (P = 0.000). Lower eyelid retraction was more severe in diffuse-type acquired epiblepharon than in central-type epiblepharon (P = 0.012). Elevation limitation was more severe in central-type acquired epiblepharon than in medial-type epiblepharon (P = 0.001). The occurrence of central-type epiblepharon was higher in TAO-associated acquired epiblepharon (20 eyelids, 30.8%) than in congenital epiblepharon (27 eyelids, 1.9%, P = 0.000). CONCLUSIONS: Acquired lower eyelid epiblepharon is one of the clinical features of patients with TAO. The association between lower eyelid retraction and acquired epiblepharon may lead to a better understanding of the cause of acquired epiblepharon in patients with TAO.

Oxidative stress profile in graves' ophthalmopathy in Indian patients.

PURPOSE: To report the oxidative stress profile in patient of Graves' ophthalmopathy and to study the effect of hormone level normalization on oxidative stress profile. METHODS: All first time reporting patients with Graves' ophthalmopathy to Department of ophthalmology CSM Medical University (erstwhile King George's Medical University) Lucknow during the period January 2006 to December 2008 formed the cohort. Before initiating treatment a proforma directed detailed history, complete ophthalmological examination and investigations were done. Blood sample for pro/antioxidant enzyme were withdrawn for study after taking an informed consent. Patients were treated with antithyroid drugs alone to achieve a stable euthyroid status for at least 6 months following which a blood sample was again withdrawn to study the pro/anti oxidant enzyme status following treatment. RESULTS: On normalization of thyroid status the values of reactive oxygen species decreased significantly (p<0.05) and levels of antioxidants also got corrected significantly (p<0.05). However both these values remained significantly (p<0.05) altered as compared to normal persons. CONCLUSION: We demonstrated that even after normalization of thyroid hormone level, the oxidative stress levels remain elevated. Moreover, activity of Superoxide Dismutase (SOD), Catalase (CAT), Glutathione reductase (GSHR), Glutathione peroxidise (GPx) showed decrease which could be attributed to altered metabolism and already prevalent deficiency of essential micronutrients like zinc, copper, mercury, and selenium in the Indian population. Hence, this gives way to the thought that the supplementation of these nutrients may have a role as an adjuvant to hormonal therapy in patients with Graves' ophthalmopathy.

Interleukin-1beta gene (IL-1beta) polymorphisms (SNP -511 and SNP +3953) in thyroid-associated ophthalmopathy (TAO) among the Polish population.

OBJECTIVE: The aim of this study was to evaluate whether the IL-1beta gene could be a genetic marker of the thyroid-associated ophthalmopathy (TAO) development. MATERIALS AND METHODS: The IL-1beta gene polymorphisms at -511 and +3953 regions in 117 TAO patients of Polish origin (ATA/NOSPECS class III or greater) and in 106 controls were studied. RESULTS: We found no significant differences in the frequencies of genotypes and allelic variants for SNP -511 and SNP +3953 between the controls and the studied groups. CONCLUSIONS: No association between the IL-1beta polymorphisms and the TAO existed, so those polymorphisms are not suitable genetic markers for TAO.

The Pro 12 Ala PPAR gamma gene polymorphism: possible modifier of the activity and severity of thyroid-associated orbitopathy (TAO).

OBJECTIVE: The PPAR gamma transcription factor, is involved in both adipogenesis and inflammation, which have been implicated in the pathogenesis of thyroid-associated orbitopathy (TAO). The aim of this study was to explore the possibility that the Pro(12)Ala polymorphism of the PPAR gamma gene, associated with a modified transcriptional activity, might be affecting the severity of TAO. SUBJECTS AND DESIGN: We studied two cohorts of patients with Graves' disease (GD): Group 1 comprised 172 patients of Dutch ethnic origin with TAO, who attended the outpatients' clinic, Department of Endocrinology and Orbital Centre of the Academic Medical Centre, Amsterdam. Group 2 comprised 93 consecutive patients with GD of Greek ethnic origin, who did not have TAO. In group 1, exophthalmometry measurements, lid oedema, diplopia (n = 172) and clinical activity score (CAS) (n = 110), always assessed by the same group of three investigators, were recorded. Autoantibody levels were measured. RESULTS: Allele frequency was 11.5%. There was no difference in the distribution of the polymorphism between GD patients with and without TAO. Among group 1 patients proptosis was significantly lower in Pro(12)Ala carriers (20.1 +/- 3.3 vs. 22.1 +/- 3.1, P = 0.003, t-test). PPAR gamma polymorphism carriers had lower TSH-Rab levels (mean rank 61.8 vs. 83.2, P = 0.015) and lower CAS (available in 110 patients) (mean rank 38.9 vs. 55.4, P = 0.022, M-W-test). The frequency of the polymorphism decreased with increasing CAS (P = 0.023 linear by linear association). Multivariate analysis (step) showed that the association of either proptosis or CAS with the PPAR gamma gene variant remained significant when age, smoking and TSH-Rab levels were taken into account (P < 0.01). CONCLUSIONS: The distribution of the Pro(12)Ala PPAR gamma gene polymorphism is equally present in patients with GD with or without TAO. Among patients with TAO this polymorphism is associated with less-severe and less-active disease.

Associations of protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene polymorphisms with susceptibility to Graves' disease in a Japanese population.

BACKGROUND: The polymorphism of the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene, which encodes an important negative regulator of T cell activation, has been reported to be associated with susceptibility to Graves' disease (GD) in Caucasians. The objective of this study was to investigate whether PTPN22 gene polymorphisms confer susceptibility to GD and Graves' ophthalmopathy (GO) in a Japanese population. METHODS: We performed a case-control study of PTPN22 gene polymorphisms in Japanese GD patients (n = 414) and healthy control subjects with no antithyroid autoantibodies or family history of autoimmune disorders (n = 231). The G-1123C polymorphism (rs2488457) in the promoter region, Arg620Trp (C1858T) polymorphism (rs2476601) in exon 14, IMS-JST146695 polymorphism (rs3789607) in intron 19, and SNP37 (rs3789604) downstream of the PTPN22 gene were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism using restriction enzymes and direct PCR sequencing methods. RESULTS: None of the GD patients or control subjects had the 1858T allele of the PTPN22 gene polymorphism. The AA-genotype and A-allele frequencies of SNP37 were significantly higher in GD patients than in control subjects (A-allele frequency: p = 0.0085, odds ratio = 1.45). The genotype frequencies and allele frequencies of the G-1123C and IMS-JST146695 polymorphisms did not differ between GD patients and control subjects. The -1123G/1858C/JST146695T/SNP37C haplotype frequency was significantly lower in GD patients than in control subjects. There were no associations between PTPN22 gene polymorphisms and GO. CONCLUSIONS: The results suggest that SNP37 of the PTPN22 gene is associated with susceptibility to GD in a Japanese population. Further studies including functional analyses are required.

The A946T polymorphism in the interferon induced helicase gene does not confer susceptibility to Graves' disease in Chinese population.

Genetic susceptibility plays a major role in the etiology of Graves' disease (GD). A recent study revealed that the A946T polymorphism (rs1990760) in interferon induced helicase (IFIH1) gene was a susceptible locus for GD. A case-control study in a Chinese population was undertaken, with 261 GD patients and 206 healthy subjects, to analyze the association of A946T polymorphism in IFIH1 gene with GD. In addition, the distribution of IFIH1 genotypes was investigated in subgroups according to the onset age and the Graves' ophthalmopathy (GO). No significant differences in the allele and genotype frequencies for A946T polymorphism were found between GD patients and healthy controls (chi2 = 2.834, P = 0.242; chi2 = 1.127, P = 0.288). The genotype-phenotype correlation was not identified either. Therefore we were unable to find the association of A946T polymorphism of the IFIH1 gene with the development of GD in a Chinese population.

Exophthalmos of patients with Graves' disease in Chinese of Taiwan.

PURPOSE: To determine the exophthalmos measurements in patients with Graves' disease (GD) and to compare with those of normal subjects among the Chinese of Taiwan. METHODS: Hertel's exophthalmometry were performed in 163 consecutive adult GD patients and 419 normal subjects. The values of exophthalmos, asymmetry, and the distance between lateral orbital rims (base) were evaluated. RESULTS: There was a significant difference between GD and normal adults for exophthalmos and asymmetry, with GD patients demonstrating a mean exophthalmos of 18.32 mm and asymmetry of 0.93 mm as compared with 13.91 and 0.55 mm for normal subjects (P<0.001). The mean value of base for GD adults (106.52 mm) is slightly greater than normal subjects (105.82 mm). There was no gender difference in exophthalmometric value or asymmetry in each group. A total of 79 (48.5%) GD patients had exophthalmos greater than the upper limit of normal Chinese in Taiwan (18.6 mm). Asymmetry over 2 mm was observed in 11 (6.7%) patients with GD but in none of the normal subjects. CONCLUSIONS: GD patients have significant exophthalmos and asymmetry compared to normal subjects. In comparison with previous studies, exophthalmos values for Chinese in Taiwan tend to be lower than those of Caucasians and black-American people, but are close to those of Korean, Japanese, Iranian, Indian, and Asian-American people. Adequate adjustment of normal and abnormal values of exophthalmos according to individual differences is important for the diagnosis of orbital morbidity and management of thyroid associated orbitopathy.