HLA-DRB3*0101 is associated with Graves' disease in Jamaicans

OBJECTIVES: Graves' disease is associated with different human leucocyte antigen (HLA) genes in different populations. This studywasdesigned to examinethe HLA class II associations with Graves' disease in Jamaicans. PATIENTS: One hundred and six Jamaicans with Graves' disease and 104 controls. DESIGN: Oligotyping for HLA-DRB1, DRB3, DQA1 and DQB1 alleles was performed using the polymerase chain reaction sequence specific oligonucleotide probe (PCR-SSOP) technique. RESULTS The frequency of HLA-DRB3 *0101 was increased significantly in the patients compared to controls (38.7% vs. 19.2%; RR = 2.72; Pc < 0.015). The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05). A high female to male ratio of Graves' disease, 25 :1, was observed. Other associated autoimmune diseases were rare and no significant HLA class II associations were found with clinical markers of disease. CONCLUSIONS: Jamaican patients with Graves' disease share the DRB3 *0101 susceptible allele and the DRB4 *01 protective allele but not the susceptible haplotype DRB1 *0301, DRB3*0101, DQA1*0501 with Caucasians.     

Propylthiouracil and carbimazole associated-antineutrophil cytoplasmic antibodies (ANCA) in patients with Graves' disease

OBJECTIVE: Propylthiouracil treatment of Graves' disease has been postulated to provoke antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aimed to investigate whether carbimazole therapy was also associated with increased risk of ANCA. DESIGN: The occurrence of ANCA and the relationship to thionamide treatment was investigated in a cross-sectional study in a consecutive series of 407 patients' with Graves' disease, 200 with Hashimoto's thyroiditis and 649 normal euthyroid subjects. MEASUREMENTS: ANCA was measured by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) for proteinase 3 and myeloperoxidase-ANCA. RESULTS: The prevalence of ANCA, as measured by IIF, was increased in the Graves' disease cohort (19.9%) compared with euthyroid controls (4.6%; P < 0.001). The prevalence of MPO-ANCA (measured by ELISA) was also increased in Graves' disease (P = 0.019). ANCA prevalence was more strongly associated with propylthiouracil treatment than carbimazole (P = 0.0265), although risk of ANCA was also higher in Graves' patients treated with carbimazole than controls (RR 2.2, P < 0.0001). ANCA positivity was not increased in patients with Hashimoto's thyroiditis. CONCLUSION: This study revealed a high prevalence of ANCA in treated patients with Graves' disease but not in those with Hashimoto's thyroiditis. Furthermore, within the Graves' disease population, ANCA development was associated with propylthiouracil usage to a greater extent than carbimazole. These findings suggest that the altered immune environment associated with autoimmune thyroid disease is not sufficient to develop ANCA but treatment with thionamides is important in promoting ANCA development.     

Thyroid fetal male microchimerisms in mothers with thyroid disorders: presence of Y-chromosomal immunofluorescence in thyroid-infiltrating lymphocytes is more prevalent in Hashimoto's thyroiditis and Graves' disease than in follicular adenomas

The presence of fetal cells in a maternal compartment is defined as fetal-maternal microchimerism, which has been detected in thyroids of mothers suffering from autoimmunity. We analyzed the immunohistology of paraffin-embedded thyroid specimen taken at surgery from 49 women with Hashimoto's thyroiditis (n = 25), Graves' disease (n = 15), or nodular or diffuse follicular adenomas (n = 9), whose childbirth history was positive for sons. By fluorescence in situ hybridization we screened for X-chromosome- and Y-chromosome-specific staining and compared the finding with human leukocyte antigen (HLA) DQ types of the mothers and, where available, their offspring. In 23 thyroids we found Y-chromosome-specific staining, which was more frequent in thyroid autoimmune disease (60% Hashimoto's thyroiditis and 40% Graves' disease) than in follicular adenomas (22.2%). There was no significant difference for HLA DQ alleles among women whose thyroids showed Y-chromosome staining and those without. However, a subgroup of all investigated microchimerism-positive mother-child pairs and women with Hashimoto's thyroiditis and Graves' disease more often had the susceptibility alleles HLA DQA1*0501-DQB1*0201 or DQB1*0301. In conclusion, fetal microchimerism is observed in thyroids of mothers with sons, and this is found more frequently in thyroid autoimmune diseases.     

Association of seasonal allergic rhinitis is high in Graves' disease and low in painless thyroiditis.

Hashimoto's thyroiditis is thought to be a T-helper cell type 1 (TH1)-dependent disease, but it is not clear whether Graves' disease is T-helper cell type 2 (TH2)-predominant or not. TH1-predominant diseases are infrequently and TH2-predominant diseases are frequently associated with allergic diseases. We examined the prevalence of seasonal allergic rhinitis to Japanese cedar pollen, a typical TH2-associated disease, in patients with Graves' disease (n = 126), painless thyroiditis (n = 46) and Hashimoto's thyroiditis (n = 88), and compared them to healthy controls (n = 766). Gender and age distribution were not different among patient groups and healthy controls, except for the higher age of patients with Hashimoto's thyroiditis. The prevalence of seasonal allergic rhinitis was significantly high in patients with Graves' disease (42.9%, p < 0.05) and low in patients with painless thyroiditis (13.0%, p < 0.01) but was not different in patients with Hashimoto's thyroiditis (26.1%) compared to that of healthy controls (32.6%). When patients with painless thyroiditis were included in Hashimoto's thyroiditis group, the prevalence of seasonal allergic rhinitis was 21.6% and significantly different from that of healthy controls (p < 0.05). These data indicate that Graves' disease is TH2 predominant and painless thyroiditis is a TH1-predominant disease. Our findings suggest that the shift from TH2 toward TH1 immunogenesis may be important for achieving earlier remission of Graves' disease.     

Autoantibody tests in autoimmune thyroid disease: a case-control study.

Both positive antinuclear antibody (ANA) and anti-DNA antibodies have been reported in patients with autoimmune thyroid disease. We sought to determine the frequency of ANA and other autoantibodies in autoimmune thyroid disease versus control subjects. We measured ANA by 2 methods (mouse liver, HEp-2), anti-dsDNA, anti-Ro, anti-La, anti-Sm, anti-RNP, and anticardiolipin in 26 patients with Hashimoto's thyroiditis, 26 patients with Graves' disease, and 26 control patients. Positive ANA by either method were more common in patients with Graves' disease than in controls (p = 0.002 and 0.05). Although common (46.2%), ANA by HEp-2 method was not found significantly more often in patients with Hashimoto's thyroiditis than in controls. Evidence for systemic autoimmune diseases was not found: patients with autoimmune thyroid did not have autoantibodies other than ANA and did not differ from controls in rheumatologic symptoms. Positive ANA using the widely accepted HEp-2 method were commonly found in both Graves' disease and Hashimoto's thyroiditis. No evidence of subclinical systemic autoimmune disease was found, either by specific autoantibody tests or by increased frequency of rheumatologic symptoms or signs.     

Polymorphism of the T cell receptor beta-chain in Graves' disease

We investigated the T cell antigen receptor constant (TCR beta) beta-chain genes of patients with Graves' disease using restriction fragment length polymorphism analysis. Genomic DNA from patients and normal subjects was digested with the restriction endonuclease Bg1 II, transferred to nylon membranes using the Southern blot technique, and hybridized with a TCR beta probe. A significant increase in the frequency of the 10.0; 9.2-kilobase heterozygous phenotype was found in GD (68.6%) vs. 42.1% in normal subjects (P = 0.003). Using the complex phenotype TCR homozygote (hetero) DR3 as a reference (odds ratio = 1.00), we found that the risk for Graves' disease was restricted to TCR beta heterozygote/DR3+ individuals (odds ratio = 8.31; chi 2 = 11.82; P = 0.0009); in the absence of TCR beta heterozygosity, DR3 was not significantly associated with the disease. These results suggest that TCR beta chain genes also are associated with susceptibility to GD and that the association is most pronounced in (or restricted to) those individuals who are HLA DR3 positive.     

Hashimoto's thyroiditis and HLA in Japanese

To investigate genetic factors involved in the pathogenesis of Hashimoto's thyroiditis (HT; goitrous autoimmune thyroiditis), HLA class I and class II antigens were analyzed in both seropositive HT (99 patients) and seronegative HT (43 patients). The frequency of HLA-DRw53 antigen was increased significantly in both seropositive HT (antigen frequency, 0.83; relative risk, 33.3; P less than 0.0002; corrected P less than 0.001) and seronegative HT (antigen frequency, 0.81; relative risk, 3.02; P less than 0.01; corrected P less than 0.05). The etiological fraction values for HLA-DRw53 in seropositive HT and seronegative HT were 0.58 and 0.54, respectively. An increased frequency of HLA-DQw4 and a decreased frequency of HLA-DQw1 were observed in patients with seronegative HT. These data suggest that susceptibility to HT is primarily associated with HLA-DRw53 and that HLA-DQ alleles may control the production of autoantibodies to the thyroid gland. The mode of inheritance of disease susceptibility for HT (controlled by a major gene in linkage disequilibrium with HLA-DRw53) was investigated by the method of Thomson and Bodmer, and it was suggested that disease susceptibility was inherited in a dominant manner.     

Influence of thyroid autoantibodies on thyroid cellular growth in vitro

Porcine thyroid follicle cells, cultured in suspension, were employed to investigate the effects of immunoglobulin preparations from patients with colloid goitre, Graves' disease or Hashimoto's thyroiditis on thyroid growth in vitro. Epidermal growth factor (EGF, 19 ng/ml) was used as a reference for maximum growth stimulation and produced a 9-fold increase in [3H]thymidine incorporation. Immunoglobulins (1000 micrograms/ml) were found to increase [3H]thymidine incorporation compared to control: from 10 normal individuals 32 +/- 4% (mean +/- SEM, % of EGF response), from 10 patients with colloid goitre 26 +/- 4% (not significantly different from normal), from 10 patients with Graves' disease 19 +/- 3% (P less than 0.05) and from 15 patients with Hashimoto's thyroiditis 11 +/- 2% (P less than 0.001). No patient immunoglobulin preparation showed activity greater than that of normal individuals. The lower growth stimulatory activity in Graves' disease and Hashimoto's thyroiditis remained after heat inactivation of serum and is thought to reflect surface binding of thyroid autoantibodies.     

Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes.

Possible genetic effects on the development of autoimmune thyroid disease were studied by analysis of restriction fragment length polymorphisms (RFLPs) of candidate genes. Peripheral blood leukocyte DNA was obtained from 65 caucasian patients with Graves' disease, 63 caucasian patients with Hashimoto's thyroiditis, and 65 caucasian controls. RFLP analysis was carried out on genomic DNA, using probes for DR beta, DQ alpha, DQ beta, DP alpha, DP beta, T-cell receptor TCR alpha, and thyroid peroxidase. The methodology allowed HLA-DR and DQ typing and provided information on specific RFLP patterns related to T cell receptor (TCR)alpha, DP alpha and -beta, and -beta, and thyroid peroxidase. HLA-DR3 frequency was significantly increased in patients with Graves' disease, as reported previously by others, but neither DNA-derived subtype of DR3 was differentially increased. HLA-DQw2 was also present in increased frequency because of its linkage disequilibrium with HLA-DR3. It is uncertain whether the primary susceptibility is with DQ, DR, or another nearby locus. Susceptibility was not related in these studies to genetic loci recognized in these studies involving DQ alpha, DP, TCR, or thyroid peroxidase. A significant linkage disequilibrium between DR3 and a specific DX alpha RFLP was observed in Graves' disease, but is believed to be representative of a generalized linkage disequilibrium between DR3 and DX alpha, rather than a specific abnormality in Graves' disease. Previous studies indicating association with specific TCR RFLPs could not be reproduced. The relative risk for carriers of HLA-DR3 subtype A in this study was 7.37-fold. RFLP analysis offers the possibility of investigating linkage in a variety of candidate genes as well as established genetic relationships for potentially important subtypes. While the significant relationship with HLA-DR3/DQw2 was reconfirmed, the involvement of other genes or haplotypes could not be established.     

The HLA–DQ associations with Graves' disease in Chinese children

OBJECTIVE: Graves' disease has been documented to be associated with different HLA genes in Caucasians and Chinese adults. The incidence of childhood Graves' disease has been reported to be high in Hong Kong Chinese. The aims of this study were to examine the HLA-DQA1 and DQB1 associations with Graves' disease in Chinese children. PATIENTS AND DESIGN: Sixty-seven Chinese children with Graves' disease (59 girls and 8 boys) and 51 racially matched healthy controls were recruited for the study. Genomic DNA was extracted from venous blood samples. HLA-DQ typings were determined by sequence-specific oligonucleotide probing of the respective enzymatically amplified gene. Frequencies of HLA-DQ alleles at each locus were compared between patients and controls using the chi 2-test. RESULTS: The frequency of HLA-DQB1.0303 was increased in the combined male and female patient group [53.7%; relative risk (RR) = 4.22; Pc = 0.005] and female patients (50.8%; RR = 3.76; Pc = 0.018) compared with that in the entire control group (21.2%). HLA-DQB1*201 was protective for Graves' disease (10.4%; RR = 0.20; Pc = 0.006). In contrast to studies in Caucasians, DQA1*0501 was not associated with susceptibility for Graves' disease in Chinese children. CONCLUSIONS: This study confirms that DQB1*0303 is a race-specific susceptible allele for Graves' disease in Chinese. Both susceptible and protective HLA-DQ alleles for Graves' disease in Chinese children are different from those in Caucasians.     

A C/T polymorphism in the 5'-untranslated region of the CD40 gene is associated with Graves' disease in Koreans.

The genetic loci conferring susceptibility to Graves' disease remain unclear. The aim of the present study was to examine a C/T polymorphism in the 5'-untranslated region of the CD40 gene and its relationship with autoimmune thyroid diseases in Koreans. The C/T polymorphism in the 5'-untranslated region of CD40 gene, clinical characteristics, and thyroid antibodies were analyzed in a series of Korean patients (132 with Graves' disease, 118 with Hashimoto's thyroiditis, and 164 normal controls). The CC genotype was significantly associated with Graves' disease (odds ratio, 1.93; 95% confidence interval, 1.21-3.09; corrected p = 0.019). On the other hand, the frequency of the TT genotype was significantly lower in Graves' patients than in controls (8% vs. 18%; odds ratio, 0.38; 95% confidence interval, 0.18-0.82; corrected p = 0.044). Allele frequencies in CD40 did not differ from controls in patients with Hashimoto's thyroiditis. In patients with Graves' disease, there were significant differences between genotypic groups in the activity of stimulating thyrotropin (TSH) receptor antibody. However, clinical characteristics and other thyroid antibodies were not significantly different. In conclusion, the C allele in the 5'-untranslated region of the CD40 gene may confer genetic susceptibility to Graves' disease in Koreans.     

Serum ferritin concentration in subacute thyroiditis

Serum concentration of ferritin was measured in 20 patients (19 women, one man) with untreated (thyrotoxic phase) subacute thyroiditis, 32 patients (21 women, 11 men) with untreated Graves' disease, 17 patients (all women) with euthyroid Hashimoto's thyroiditis, 12 patients (all women) with hepatitis A (HAV), eight patients (all women) with pneumonia, and 59 normal controls (30 women, 29 men). In female patients with subacute thyroiditis, the serum concentration of ferritin was 163.6 +/- 116.3 micrograms/L (after log transformation, 2.12 +/- 0.31 micrograms/L, mean +/- SD), which was significantly higher than values in female Graves' disease (P less than .05), Hashimoto's thyroiditis (P less than .001), pneumonia (P less than .05), and healthy subjects (P less than .001), being 97.9 +/- 71.9 micrograms/L (after log transformation, 1.85 +/- 0.42 micrograms/L), 51.6 +/- 53.0 micrograms/L (after log transformation, 1.48 +/- 0.50 micrograms/L), 88.2 +/- 56.3 micrograms/L (after log transformation, 1.86 +/- 0.30 micrograms/L), and 25.2 +/- 7.4 micrograms/L (after log transformation; 1.16 +/- 0.10 micrograms/L), respectively, but was not significantly different with HAV, being 368.3 +/- 514.0 micrograms/L (after log transformation, 2.32 +/- 0.47 micrograms/L). In a male with subacute thyroiditis, the serum concentration of ferritin was 521.8 micrograms/L (after log transformation, 2.72 micrograms/L), which was higher than +/- 3 SD and +/- 1 SD of the levels in healthy males (93.0 +/- 55.9 micrograms/L; after log transformation, 1.89 +/- 0.27 micrograms/L) and male Graves' disease patients (257.0 +/- 195.5 micrograms/L; after log transformation, 2.28 +/- 0.38 micrograms/L), respectively. Elevated serum ferritin concentration significantly declined with treatment by either aspirin or prednisolone (paired t test, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Polymorphism in the transmembrane region of the major histocompatibility complex class I chain-related gene A: association of five GCT repetitions with Graves' disease in children.

Graves' disease is an autoimmune disease involving a complex interplay of multiple genetic and environmental influences. An association between the disorder and the major histocompatibility complex (MHC; human leukocyte antigen [HLA]) region has long been reported. The major histocompatibility complex class I chain-related gene A (MICA) has a triplet repeat polymorphism in the transmembrane region consisting of six alleles. For this study, the polymorphism in question was analyzed for 129 unrelated children with Graves' disease (97 girls and 32 boys, 10.0 +/- 3.0 years of age) and 396 randomly selected, unrelated subjects (205 females, 191 males, 8.4 +/- 13.5 years of age). The frequencies of genotype A5/A5 and A5/A5.1 were significantly higher in patients than in controls (relative risk [RR] = 2.49, 95% confidence interval [CI] 1.52-4.10, p = 0.00024, pc = 0.0035 and RR = 2.13, 95% CI 1.31-3.47, p = 0.0020, pc = 0.030; respectively). The frequency of genotype A5.1/A5.1 was significantly lower in patients than in controls (RR = 0.09, 95% CI 0.01-0.66, p = 0.0030, pc = 0.044). Allele frequency for allele A5 was significantly higher for children with Graves' disease compared to controls (RR = 2.12; 95% CI = 1.59-2.82; p = 1.9 x 10(-7); pc = 9.5 x 10(-7)). This study demonstrates that MICA allele A5 confers the risk for Graves' disease.     

Vitamin D 1alpha-hydroxylase (CYP1alpha) polymorphism in Graves' disease,Hashimoto's thyroiditis and type 1 diabetes mellitus

OBJECTIVE: The vitamin D endocrine system plays a role in the regulation of (auto)immunity and cell proliferation. Vitamin D 1alpha-hydroxylase (CYP1alpha) is one of the key enzymes regulating both systemic and tissue levels of 1,25-dihyroxyvitamin D(3) (1,25(OH)(2)D(3)). Administration of 1,25(OH)(2)D(3), whose serum levels were found to be reduced in type 1 diabetes and thyroid autoimmunity, prevents these diseases in animal models. We therefore investigated a recently reported CYP1alpha polymorphism for an association with type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. DESIGN AND METHODS: Four hundred and seven Caucasian pedigrees with one offspring affected by either type 1 diabetes (209 families), Graves' disease (92 families) or Hashimoto's thyroiditis (106 families) were genotyped for a C/T polymorphism in intron 6 of the CYP1alpha gene on chromosome 12q13.1-13.3 and transmission disequilibrium testing (TDT) was performed. Subsets of affected offspring stratified for HLA-DQ haplotype were compared using chi(2) testing. RESULTS: There was no deviation from the expected transmission frequency in either type 1 diabetes mellitus (P=0.825), Graves' disease (P=0.909) or Hashimoto's thyroiditis (P=0.204). However, in Hashimoto's thyroiditis the CYP1alpha C allele was significantly more often transmitted to HLA-DQ2(-) patients (27 transmitted vs 14 not transmitted; TDT: P=0.042) than expected. The C allele was less often transmitted to HLA-DQ2(+) patients (9 transmitted vs 12 not transmitted; TDT: P=0.513), although the difference was not significant (chi(2) test: P=0.143). A similar difference was observed in type 1 diabetes between offspring with high and low risk HLA-DQ haplotypes (chi(2) test: P=0.095). CONCLUSIONS: The CYP1alpha intron 6 polymorphism appears not to be associated with type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. A potential association in subsets of patients with type 1 diabetes and Hashimoto's thyroiditis should be further investigated as well as its functional implications.     

Thyroid vascularity and blood flow are not dependent on serum thyroid hormone levels: studies in vivo by color flow doppler sonography

OBJECTIVE: Thyroid blood flow is greatly enhanced in untreated Graves' disease, but it is not known whether it is due to thyroid hormone excess or to thyroid hyperstimulation by TSH-receptor antibody. To address this issue in vivo patients with different thyroid disorders were submitted to color flow doppler sonography (CFDS). SUBJECTS AND METHODS: We investigated 24 normal subjects, and 78 patients with untreated hyperthyroidism (49 with Graves' hyperthyroidism, 24 with toxic adenoma, and 5 patients with TSH-secreting pituitary adenoma (TSHoma)), 19 patients with thyrotoxicosis (7 with thyrotoxicosis factitia, and 12 with subacute thyroiditis), 37 euthyroid patients with goitrous Hashimoto's thyroiditis, and 21 untreated hypothyroid patients with Hashimoto's thyroiditis. RESULTS: Normal subjects had CFDS pattern 0 (absent or minimal intraparenchimal spots) and mean intraparenchimal peak systolic velocity (PSV) of 4.8+/-1.2cm/s. Patients with spontaneous hyperthyroidism due to Graves' disease, TSHoma, and toxic adenoma had significantly increased PSV (P<0.0001, P=0.0004, P<0.0001 respectively vs controls) and CFDS pattern. Patients with Graves' disease had CFDS pattern II (mild increase of color flow doppler signal) in 10 (20%) and pattern III (marked increase) in 39 cases (80%). Mean PSV was 15+/-3cm/s. Patients with toxic adenoma had CFDS pattern I (presence of parenchymal blood flow with patchy uneven distribution) in 2 (8%), pattern II in 16 (70%) and pattern III in 5 (22%). Mean PSV was 11+/-2.4cm/s. Patients with TSHoma showed CFDS pattern I in one case (20%) and pattern II in 4 (80%). Mean PSV was 14.8+/-4.2cm/s. Patients with thyrotoxicosis had normal PSV (4.2+/-1. 1cm/s in subacute thyroiditis, 4+/-0.8cm/s in thyrotoxicosis factitia, P=not significant vs controls) and CFDS pattern 0. Untreated euthyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern 0, and mean PSV (4.3+/-0.9cm/s; P=not significant vs controls). Untreated hypothyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern I in 14 cases (67%), pattern II in 4 (19%) and pattern 0 in 3 (14%) and mean PSV (5.6+/-1. 4cm/s) was higher than that of controls (P=0.026). CONCLUSIONS: An increase in both intrathyroidal vascularity and blood velocity was observed in patients with spontaneous hyperthyroidism but not in thyrotoxicosis due to either ingestion of thyroid hormones or to a thyroidal destructive process. The slightly increased vascularity and blood velocity observed in patients with hypothyroid Hashimoto's thyroiditis suggests that thyroid stimulation by either TSH-receptor antibody or TSH is responsible for the increased thyroid blood flow.     

A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans

BACKGROUND: CYP27B1 hydroxylase catalyzes the conversion of 25 hydroxyvitamin D(3) (25OHD(3)) to 1,25(OH)(2)D(3), the most active natural vitamin D metabolite, which plays a role in the regulation of immunity and cell proliferation. We therefore investigated two single nucleotide polymorphisms in the CYP27B1 hydroxylase gene for an association with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus. METHODS: Patients with Addison's disease (n=124), Hashimoto's thyroiditis (n=139), Graves' disease (n=334), type 1 diabetes mellitus (n=252) and healthy controls (n=320) were genotyped for the promoter (-1260) C/A polymorphism and for the intron 6 (+2838) C/T polymorphism of the CYP27B1 gene. Patients and controls were compared using genotype-wise and allele-wise X(2) testing. RESULTS: A significant association was found between allelic variation of the promoter (-1260) C/A polymorphism and Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus (P=0.0062, P=0.0173, P=0.0094 and P=0.0028 respectively). Significant differences were also observed for the intron 6 (+2838) C/T polymorphism (P=0.0058) in Hashimoto's thyroiditis but not for the other autoimmune endocrine diseases. CONCLUSIONS: The CYP27B1 promoter (-1260) C/A polymorphism appears to be associated with endocrine autoimmune diseases but the CYP27B1 intron 6 (+2838) C/T polymorphism appears to be associated only with Hashimoto's thyroiditis. These results imply a regulatory difference of the CYP27B1 hydroxylase to predispose to endocrine autoimmunity.     

Prevalence and Relative Risk of Other Autoimmune Diseases in Subjects with Autoimmune Thyroid Disease

Background

Common autoimmune disorders tend to coexist in the same subjects and to cluster in families.

Methods

We performed a cross-sectional multicenter study of 3286 Caucasian subjects (2791 with Graves' disease; 495 with Hashimoto's thyroiditis) attending UK hospital thyroid clinics to quantify the prevalence of coexisting autoimmune disorders. All subjects completed a structured questionnaire seeking a personal and parental history of common autoimmune disorders, as well as a history of hyperthyroidism or hypothyroidism among parents.

Results

The frequency of another autoimmune disorder was 9.67% in Graves' disease and 14.3% in Hashimoto's thyroiditis index cases (P = .005). Rheumatoid arthritis was the most common coexisting autoimmune disorder (found in 3.15% of Graves' disease and 4.24% of Hashimoto's thyroiditis cases). Relative risks of almost all other autoimmune diseases in Graves' disease or Hashimoto's thyroiditis were significantly increased (>10 for pernicious anemia, systemic lupus erythematosus, Addison's disease, celiac disease, and vitiligo). There was relative “clustering” of Graves' disease in the index case with parental hyperthyroidism and of Hashimoto's thyroiditis in the index case with parental hypothyroidism. Relative risks for most other coexisting autoimmune disorders were markedly increased among parents of index cases.

Conclusion

This is one of the largest studies to date to quantify the risk of diagnosis of coexisting autoimmune diseases in more than 3000 index cases with well-characterized Graves' disease or Hashimoto's thyroiditis. These risks highlight the importance of screening for other autoimmune diagnoses if subjects with autoimmune thyroid disease present with new or nonspecific symptoms.     

Decreased suppressor T-lymphocytes in autoimmune thyroid diseases detected by monoclonal antibodies

Monoclonal antibodies reacting with cell surface antigens of helper (T4), suppressor (T8) T cells and common T-cell antigen (T3) were used by an immunofluorescence technique to enumerate peripheral T-lymphocytes in 42 patients with Graves' disease and 16 patients with Hashimoto's thyroiditis. The percentages of total T cells (cells which react with anti-T3) and helper/inducer cells (cells which react with anti-T4) among peripheral mononuclear cells in Graves' and Hashimoto's patients were not significantly different from those found in normal controls, except for a decrease in cells which react with anti-T3 in toxic Graves' disease without medication. The most important finding was a decrease in the percentage of cytotoxic/suppressor T cells (cells which react with anti-T8) in toxic Graves' disease and Hashimoto's thyroiditis. In patients with Graves' disease who were hyperthyroid or euthyroid on propylthiouracil treatment and euthyroid after radioactive iodide treatment, the percentage of cells which react with anti-T8 was also decreased, but this did not reach statistical significance. These findings support the hypothesis of defects in suppressor T-lymphocytes in autoimmune thyroid diseases.     

Immunogenetics of Hashimoto's and Graves' diseases

Haplotypes of the human major histocompatibility complex (HLA) and the immunoglobulin allotype (Gm) were analyzed in all 243 members of 37 families in which 2 or more first degree relatives had Graves' disease. In 10 families with 70 members where 1 or more first degree relatives had Hashimoto's disease, 26 (37%) had Graves' disease, and 14 (20%) had Hashimoto's disease. In the other 27 families, consisting of 173 members, 70 (40%) had Graves' disease, and none had Hashimoto's disease. The disease-associated haplotypes of HLA and Gm for each family were identified by determining the haplotypes concordant in 2 members with Graves' disease. In 10 families with Graves' and Hashimoto's diseases, all 14 members with Hashimoto's disease had the same disease-associated haplotypes of both HLA and Gm as had members with Graves' disease in each family. Among 96 members with Graves' disease in 37 families, 74 were used for the determination of the disease-associated haplotypes. In the remaining 22 members with Graves' disease, 21 had both disease-associated haplotypes in their families. Our findings in these families suggest that 1) in Hashimoto's disease as in Graves' disease, two genes linked to HLA and Gm, respectively, control the susceptibility of the disease; 2) common immunogenetic factors are involved in the pathogenesis of both Hashimoto's and Graves' disease, and 3) those who do not have immunogenetic factors are very unlikely to develop Hashimoto's or Graves' disease.     

Changes in thyroid-stimulating immunoglobulins during antithyroid therapy

Thyroid-stimulating immunoglobulin (TSI) activity was measured by radioreceptor assay in sera from patients with Graves' disease, Hashimoto's thyroiditis, and thyroid cancer. In untreated Graves' disease (47 cases), TSI index was significantly lower [76.7 +/- 1.4 (SE)] than the average of a normal control group (30 cases; 94.4 +/- 1.9). In untreated Hashimoto's thyroiditis (25 cases), it was also significantly lower (83.0 +/- 2.4). In patients with thyroid cancer (19 cases), there was no significant difference from normal controls. After 131I treatment, the TSI index in Graves' disease decreased during 2--4 months, then increased and reached normal levels in 1 yr. During propylthiouracil treatment, the TSI index increased and reached a normal level in 5--6 months without the decreasing phase seen after 131I treatment. Free T4 index values were gradually decreased by both treatments. There was no significant relationship between TSI index and thyroid antibodies (microsomal antibodies and thyroglobulin antibodies) in untreated Graves' disease or Hashimoto's thyroiditis. It is concluded that 1) in the sera of patients with Graves' disease and Hashimoto's thyroiditis, there are immunoglobulin Gs that can displace TSH binding to thyroid membranes; 2) these immunoglobulins Gs are different from the classic antithyroid antibodies; and 3) 131T treatment of Graves' disease may enhance TSI production during the first 1--2 months after therapy.