Age related changes of soluble Fas, Fas ligand and Bcl-2 in autoimmune thyroid diseases

INTRODUCTION: Apoptosis plays a pivotal role in the regulation of immune mechanisms in the pathogenesis of autoimmune thyroid diseases (AITD). The prevalence of AITD increases with age. Purpose to compare soluble Fas, FasL and Bcl-2 in Graves disease (GD) and Hashimoto thyroiditis (HT) in relation to the age of the studied patients. MATERIAL AND METHODS: 3 groups of subjects: 1/25 patients with GD in euthyreosis on methimazol 2/27 patients with ChH in euthyreosis on levothyroxine. 3/12 healthy volunteers age and sex-matched to group 1-2. The serum levels of Fas, FasL and Bcl-2 were determined by the ELISA kit. RESULTS: We found positive correlations between sFas and age in GD patients (r = 0.35; p < 0.05). In GD patients we found a negative correlation between sFasL and age in all studied patients with AITD (r = -0.34; p < 0.01). We also found a negative correlation between sBcl-2 and age in HT patients (r = -0.42; p < 0.05). CONCLUSIONS: Fas/FasL and Bcl-2 signaling pathways seem to be age-related and may explain, at least in part, milder course of Graves disease in elderly patients and increased prevalence of Hashimoto disease in this group of subjects.     

Autoimmune thyroid disease in patients with vitiligo: prevalence study in India

ObjectiveTo identify the prevalence of autoimmune thyroid disease (AITD) in Asian Indian patients with vitiligo and to compare the clinical profile between thyroid peroxidase (TPO) antibody-positive and TPO antibodynegative groups.MethodsIn this cross-sectional, case-controlled study, 50 patients with vitiligo (29 women and 21 men) were included. Patients with previous disorders, irradiation, or surgical procedures involving the thyroid were excluded from the study. All participants underwent a complete physical examination, and a single fasting blood sample was analyzed for thyroid function (triiodothyronine, thyroxine, thyroid-stimulating hormone, and TPO and thyroglobulin antibodies), inflammatory and immunologic markers (erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor), and serum calcium, phosphorus, and alkaline phosphatase concentrations. All patients underwent thyroid ultrasonography, and the data were analyzed by appropriate statistical methods.ResultsThe mean age of the study participants was 42.7 ± 17 years, and 14 of 50 patients (28%) had TPO antibody positivity. A goiter was present in 11 of 50 patients, and the thyroid volume by ultrasonography was similar between the 2 groups. Subclinical hypothyroidism was found in 14 of 50 patients (28%) but more frequently in the TPO antibody-positive group (8 of 14 or 57%) than in the TPO antibody-negative group (6 of 36 or 17%). The prevalence of AITD was 20 of 50 patients (40%) when the TPO antibody-positive group and those with subclinical hypothyroidism were considered collectively. None of the patients had overt hypothyroidism or hyperthyroidism. All other clinical, biochemical, and inflammatory variables did not differ significantly between the TPO antibody-positive and antibody-negative groups.ConclusionOur data showed a 40% prevalence of thyroid disease in patients with vitiligo in India. The risk is exacerbated in patients with thyroid autoimmunity; thus, regular screening of patients with vitiligo for AITD is needed. (Endocr Pract. 2012;18:194-199)     

X chromosome monosomy: a common mechanism for autoimmune diseases

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y alpha-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 +/- 0.3% and 4.3 +/- 0.3%, respectively, vs 2.9 +/- 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.     

Coeliac disease in endocrine diseases of autoimmune origin

Abstract Coeliac disease (CD, sometimes called gluten-sensitive enteropathy or nontropical sprue) is an inflammatory disorder of the small intestine of autoimmune origin. It occurs in genetically predisposed people and is induced by a gluten protein, which is a component of wheat. The prevalence of histologically confirmed CD is estimated in screening studies of adults in the United States and Europe to be between 0.2% and 1.0%. The results of previous studies have indicated that the prevalence of CD is increased in patients with other autoimmune disorders such as: autoimmune thyroid diseases, type 1 diabetes mellitus, and Addison's disease. A coincidence of the above diseases constitutes autoimmune polyglandular syndrome (APS). The high prevalence of CD in APS is probably due to the common genetic predisposition to the coexistent autoimmune diseases. The majority of adult patients have the atypical or silent type of the disease. This is the main reason why CD so often goes undiagnosed or the diagnosis is delayed. CD, if undiagnosed and untreated, is associated with many medical disorders including haematological (anaemia), metabolical (osteopenia/osteoporosis), obstetric-gynaecological (infertility, spontaneous abortions, late puberty, early menopause), neurological (migraine, ataxia, epilepsy) as well as with an increased risk of malignancy, especially: enteropathy-associated T-cell lymphoma, small intestine adenocarcinoma, and oesophageal and oropharyngeal carcinomas. Early introduction of a gluten-free diet and lifelong adherence to this treatment decreases the risk of these complications.     

Susceptibility alleles and haplotypes of human leukocyte antigen DRB1, DQA1, and DQB1 in autoimmune polyglandular syndrome type III in Japanese population

BACKGROUND: It has been reported that HLA class II haplotypes DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0901-DQA1*0302-DQB1*0303 are major susceptibility haplotypes for type 1 diabetes mellitus (DM) in Japanese population. However, little has been reported on the susceptibility HLA class II haplotypes in Japanese patients with autoimmune polyglandular syndrome type II and type III (APS III). PATIENTS AND METHODS: HLA class II haplotypes of DRB1-DQA1-DQB1 in 31 patients with APS III, 14 patients with Hashimoto's thyroiditis alone, and 15 patients with Graves' disease alone were examined in Japanese population. APS III patients were divided into three groups (A, B, and C) depending on the combination of autoimmune endocrine diseases. RESULTS: In 13 APS III patients with both Hashimoto's thyroiditis and type 1 DM (group A), the haplotype frequencies of the HLA DRB1*0802-DQA1*0401-DQB1*0402 and DRB1*0901-DQA1*0302-DQB1*0303 were significantly higher than in the controls. In patients with Hashimoto's thyroiditis alone, the haplotype frequency of DRB1*0901-DQA1*0302-DQB1*0303 was significantly higher than in controls, whereas the frequency of DRB1*0802-DQA1*0401-DQB1*0402 did not differ significantly from those in the controls. In 11 APS III patients with both Graves' disease and type 1 DM (group B), the haplotype frequencies of HLA DRB1*0405-DQA1*0303-DQB1*0401 and DRB1*0802-DQA1*0301-DQB1*0302 were significantly higher than in controls. In patients with Graves' disease alone, the haplotype frequency of DRB1*0803-DQA1*0103-DQB1*0601 were significantly higher than those in controls, suggesting that the susceptibility haplotypes for group B APS III differed from those for Graves' disease alone. In 7 APS III patients with both autoimmune thyroid diseases and pituitary disorders (group C), the haplotype frequency of HLA DRB1*0405-DQA1*0303-DQB1*0401 was significantly higher than in controls. CONCLUSIONS: Susceptible HLA class II haplotypes of DRB1-DQA1-DQB1 for APS III differ between the Japanese and Caucasian populations. More interestingly, the susceptible HLA class II haplotypes differ among the three types of Japanese APS III and are not merely a combination of susceptibility haplotypes of each endocrine disease.     

Analysis of heat shock protein polymorphisms in a large family with autoimmune thyroid diseases

Graves disease and Hashimoto's thyroiditis are autoimmune thyroid diseases (AITD) in which the genetic contribution is complex. The purpose of this work was to analyze the influence of hsp70 gene polymorphisms on the susceptibility to AITD. The hsp 70-2 and hsp 70-hom polymorphism was analyzed, by PCR-RFLP using PstI and NcoI enzymes, respectively, in 40 patients affected with AITD and 38 related healthy individuals belonging to a large consanguineous family named Akr. The transmission disequilibrium test (TDT) was applied on nuclear families, deduced from the Akr pedigree, with at least one heterozygous parent for each studied polymorphism. The corresponding x2 values for hsp 70-2 and hsp 70-hom were, respectively, of 0.52, p > 0.05 and 2.77, p > 0.05. Our data indicated lack of association between these hsp polymorphisms and AITD in this large family.     

Paraoxonase and arylesterase levels in autoimmune thyroid diseases

Objective: The aim of this study was to evaluate serum paraoxonase-1 (PON1) activity and its association with oxidative stress in autoimmune thyroid disease (AITD).

Methods: A total of 50 patients with AITD, including 25 with Hashimoto's thyroiditis and 25 with Graves’ disease were enrolled. The control group comprised 27 healthy subjects. Blood samples were obtained in the euthyroid period and 3 months after initiation of medical treatment. Serum samples from patients with AITD and the healthy control group were analyzed for basal PON1, salt-stimulated PON1, and arylesterase (ARE) activities, along with lipid hydroperoxide (LOOH) and total free sulfhydryl (–SH) levels.

Results: Serum PON1 activities and –SH levels were significantly lower (P?<?0.001, for each), whereas LOOH levels were significantly higher (P?<?0.001, for each) in patients with AITD, compared to the control group. We observed no significant differences in ARE levels between the patient and healthy control groups (P?>?0.05). PON1 activity was positively correlated with –SH (r?=?0.522, P?<?0.001) and negatively correlated with LOOH (r?=??0.487, P?<?0.001). PON1 phenotype distribution of the subjects was not significantly different among the three groups (P?=?0.961).

Conclusions: Serum PON1 activity is decreased in patients with AITD, and correlated positively with –SH, a well-known antioxidant, and negatively with LOOH, an index of lipid oxidation.     

Anti-GAD-positive patients with type 1 diabetes mellitus have higher prevalence of autoimmune thyroiditis than anti-GAD-negative patients with type 1 and type 2 diabetes mellitus

The aim of our study was to evaluate antibodies against thyroglobulin (anti-TG) and thyroid peroxidase (anti-TPO) - markers of autoimmune thyroiditis - in several groups of adult patients with type 1 and type 2 diabetes mellitus (DM). We were particularly interested whether the presence of thyroid antibodies is related to the positivity of glutamic acid decarboxylase antibodies (anti-GAD). We found elevated anti-GAD in 46 % (97/210) patients with type 1 DM. All patients with type 2 diabetes were anti-GAD-negative. At least one thyroid antibody (anti-TG and/or anti-TPO) was found in 30 % (62/210) patients with type 1 DM and 27 % (22/83) type 2 diabetes patients. The patients with type 1 DM were further grouped according to their anti-GAD status. The anti-GAD-positive patients had a higher prevalence of anti-TG antibodies than the anti-GAD-negative patients (25 % vs. 12 %, p=0.03) as well as anti-TPO antibodies (32 % vs. 12 %, p<0.001). At least one thyroid antibody was detected in 39 % (38/97) of anti-GAD-positive but only in 21 % (24/113) of anti-GAD-negative patients with type 1 DM (p=0.006). No significant difference in the frequency of thyroid antibodies was found between anti-GAD-negative patients with type 1 and type 2 DM (21 % vs. 27 %, p=0.4). The groups with or without thyroid antibodies in both type 1 and type 2 diabetic patients did not differ in actual age, the age at diabetes onset, duration of diabetes, body mass index or HbA1c level. Patients with elevated thyroid antibodies had significantly higher levels of TSH than those without thyroid antibodies (1.86 vs. 3.22 mIU/l, p=0.04 in type 1 DM; 2.06 vs. 4.89 mIU/l, p=0.003 in type 2 DM). We conclude that there is a higher frequency of thyroid-specific antibodies in anti-GAD-positive adult patients with type 1 DM than in anti-GAD-negative patients or in patients with type 2 DM. Patients with or without thyroid antibodies do not differ in age, DM onset and duration, BMI or HbA1c. Thyroid antibodies-positive patients have higher levels of thyroid stimulating hormone (TSH).     

The thyroglobulin gene as the first thyroid-specific susceptibility gene for autoimmune thyroid disease

Recent linkage and association studies provide evidence for thyroglobulin (Tg) being an autoimmune thyroid disease (AITD) susceptibility gene. The Tg locus has been reported to be linked with AITD in two independent studies, and further analysis demonstrated that markers within the Tg gene were associated with AITD. Furthermore, missense single-nucleotide polymorphisms (SNPs) in the Tg gene were shown to be associated with autoimmune thyroiditis in both mice and humans. If Tg is confirmed as a susceptibility gene for AITD, it could provide a novel therapeutic target.     

The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders.

H. pylori infection is putatively associated with extra-digestive disorders and may also play a role in the development of autoimmune thyroid diseases (ATD). It was recently found that monoclonal antibodies to an H. pylori strain with cagA-positivity reacted with follicular cells of the thyroid gland, and that an H. pylori organism possessing the cag pathogenicity island carried a gene encoding for an endogenous peroxidase. The aims of this study was (1); To ascertain whether the infection by strains endowed with an increased inflammatory potential (those expressing CagA) could further enhance the risk of developing ATD (2); To verify the possible existence of an immune cross-reactivity between autoantibodies to peroxidase and thyroglobulin and H. pylori antigens (3). To establish whether thyroid colloid antigens could cross-react with an anti-H. pylori serum. The study was partly designed retrospectively. We examined 41 consecutive women with ATD, and, as a control, 33 consecutive age- and socio-economic class-matched women without autoimmune thyroid disorders, living in the same area as patients, occurred at the same institution in the same period (six months). Both patients and controls were examined serologically for H. pylori infection and CagA status by Western blotting. Some serum samples were absorbed with H. pylori to determine whether the antibody levels decreased. Colloid proteins were resolved electrophoretically and matched with a hyperimmune serum raised in rabbits against a CagA-positive H. pylori. Thirty-two patients (78.0%) tested seropositive for H. pylori infection, vs. 16 controls (48.4%) (P = 0.008, OR = 3.78, RR = 1.61). The prevalence of anti-CagA antibodies was 71.8% in infected patients, and 50% in infected controls (P = 0.161, n.s.). The overall prevalence of infection by CagA-positive H. pylori was significantly higher in patients with ATD (23/41, or 56.0%) than that in controls (8/33, or 24.2%) (P = 0.006, OR = 3.99, RR = 2.31). The other tests gave negative or inexplicable results. In conclusion: CagA-positive H. pylori infection increases the risk of ATD development.     

Chemokines and autoimmune thyroid diseases.

Chemokines are a family of small, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with their seven-transmembrane, G protein-coupled receptors. Their major function is the recruitment of leukocytes to inflammation sites, but they also play roles in tumor growth, angiogenesis, organ sclerosis, and autoimmunity. A variety of evidence has accumulated to support the concept that thyroid follicular cells as well as intrathyroidal lymphocytes are able to produce CC and CXC chemokines, which, in turn, promote the initiation and maintenance of an inflammatory process resulting in autoimmune thyroid diseases (AITD). Overexpression of several chemokines in AITD has been demonstrated. Moreover, alterations of CCL2, CCL5, CXCL9, and CXCL10 have been shown in circulation of many patients with AITD. In subjects with Graves' disease, antithyroid drug treatment, radioactive iodine ablation, and thyroidectomy can significantly reduce CXCL10 levels. The measurement of chemokines in serum of AITD patients might provide a useful parameter for the evaluation and prediction of disease activity and progression. Further experimental and clinical studies will expand our understanding of the clinical implications of chemokine detection and the effects of chemokines on the pathogenesis of AITD.     

Immunological abnormality of peripheral blood B cells in patients with autoimmune thyroid disease

We investigated the response to immunoglobulin G-secreting cells (ISC) by peripheral blood mononuclear cells (PB-MNC) and purified B cells following stimulation with Staphylococcus aureus Cowan 1 (SAC) or with B cell stimulatory factor 2 (interleukin 6: IL-6), using the reverse hemolytic plaque assay in an attempt to clarify the immunological functions of peripheral blood B cells in patients with autoimmune thyroid disease (AITD). ISC response by PB-MNC following stimulation with SAC was significantly decreased in patients in the hyperthyroid state of Graves' disease and Hashimoto's thyroiditis as compared with that of normal controls. The difference in SAC-response was not significant between patients with euthyroid state of Graves' disease and normal controls. ISC response by PB-MNC following stimulation with SAC exhibited a reciprocal relationship to TRAb in patients with Graves' disease. Using purified B cells, some spontaneous ISC response without SAC stimulation was observed in patients in the hyperthyroid state of Graves' disease and Hashimoto's thyroiditis. This spontaneous ISC response was further enhanced by IL-6. These results suggest that in organ-specific autoimmune diseases such as AITD, immunological abnormalities exist in B cells and some B cells are nonspecifically activated in the immunologically active state.     

IgA and IgG antigliadin,IgA anti-tissue transglutaminase and antiendomysial antibodies in patients with autoimmune thyroid diseases and their relationship to thyroidal replacement therapy

Celiac disease is a chronic illness of the small bowel caused by gliadin intolerance in genetically predisposed subjects. The aim of this study was to investigate serum levels of IgA and IgG antigliadin antibodies, IgA antiendomysial antibodies, and IgA anti-tissue transglutaminase antibodies in 169 patients with autoimmune thyroid diseases, i.e. chronic thyroiditis and Graves' disease. Antiendomysial antibodies were positive in 2 out of 169 persons (1.18%), IgA antigliadin antibodies in 15.98%, IgG antigliadin antibodies in 51.48%, and IgA anti-tissue transglutaminase in 14.79%. The prevalence of positivity was higher compared to the 1312 control blood donors described in our previous study (Vancíková et al. 2002) (p<0.05). Patients with chronic thyroiditis treated with a high replacement dosage of levothyroxin (125-200 microg daily) had higher serum levels of IgA antigliadin antibodies in comparison with patients treated with a lower dosage (50-100 microg daily) (medians: 13.00 vs. 19.69, p=0.033). We found a negative correlation of IgA anti-tissue transglutaminase antibodies and total calcium serum levels (r = -0.480, p=0.0236, n=22). We can conclude that in persons with autoimmune thyropathy there is a high prevalence of positive antigliadin, anti-tissue transglutaminase and antiendomysial antibodies. Latent celiac disease may lead to impaired resorption of therapeutically administered levothyroxine, calcium, or other substances.     

Circulating chemokines in patients with autoimmune thyroid diseases.

Chemokines are a group of small proteins that recruit different leukocyte subtypes to sites of inflammation and play important roles in initiating and maintaining immunological responses in autoimmune endocrine diseases including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies have found increased gene and protein expression of different kinds of chemokines not only within the thyroid gland but also within thyroid cells in GD or HT patients. A few studies have determined serum levels of chemokines, with conflicting results. We measured circulating concentrations of CCL2, CCL5, CXCL9, and CXCL10 in patients with GD, HT, and nontoxic nodular thyroid disease (NNT). While CCL2 and CXCL9 concentrations were comparable in patients with either AITD or NNT, CCL5 was significantly increased in GD patients compared with HT or NNT subjects. In contrast, CXCL10 levels were lower in patients with GD, but the difference was statistically significant only when compared with patients with HT (p=0.0018). Importantly, GD patients who relapsed or went into remission had significantly different levels of CXCL9 (p=0.0252). Serum levels of CCL2, CCL5, CXCL9, and CXCL10 did not reveal any correlation with thyroid volume; with the levels of thyrotropin (TSH), FT3, or FT4; or with the titers of TSH receptor antibody and thyroperoxidase antibody. These data suggest that the expression patterns of chemokines in various thyroid diseases differ from each other, which may reflect the distinct immune responses in HT and GD.     

Multiple SNPs in intron 41 of thyroglobulin gene are associated with autoimmune thyroid disease in the Japanese population

BACKGROUND: The etiology of the autoimmune thyroid diseases (AITDs), Graves' disease (GD) and Hashimoto's thyroiditis (HT), is largely unknown. However, genetic susceptibility is believed to play a major role. Two whole genome scans from Japan and from the US identified a locus on chromosome 8q24 that showed evidence for linkage with AITD and HT. Recent studies have demonstrated an association between thyroglobulin (Tg) polymorphisms and AITD in Caucasians, suggesting that Tg is a susceptibility gene on 8q24. OBJECTIVES: The objective of the study was to refine Tg association with AITD, by analyzing a panel of 25 SNPs across an extended 260 kb region of the Tg. METHODS: We studied 458 Japanese AITD patients (287 GD and 171 HT patients) and 221 matched Japanese control subjects in association studies. Case-control association studies were performed using 25 Tg single nucleotide polymorphisms (SNPs) chosen from a database of the Single Nucleotide Polymorphism Database (dbSNP). Haplotype analysis was undertaken using the computer program SNPAlyze version 7.0. PRINCIPAL FINDINGS AND CONCLUSIONS: In total, 5 SNPs revealed association with GD (P<0.05), with the strongest SNP associations at rs2256366 (P?=?0.002) and rs2687836 (P?=?0.0077), both located in intron 41 of the Tg gene. Because of the strong LD between these two strongest associated variants, we performed the haplotype analysis, and identified a major protective haplotype for GD (P?=?0.001). These results suggested that the Tg gene is involved in susceptibility for GD and AITD in the Japanese.     

HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III.

No significant differences were reported for the frequency of DR3-DQ2 and DR4-DQ8 haplotypes in a recent study of one of the largest cohorts worldwide of patients with isolated Addison's disease compared to patients with APS II. However, previous studies had suggested that the HLA-DQ genes, especially DQA1*0102, may be a genetic marker for resistance to autoimmune thyroid disease, which is the most frequent disease in APS II or III. Until now, HLA-DQA1 alleles have not been systematically investigated in APS. We determined the HLA-DR and HLA-DQA1 association in 112 unrelated patients with APS II (n = 29), APS III (n = 83) and 184 unrelated patients with single-component diseases without further manifestations of APS: Graves' disease (n = 70), Hashimoto's thyroiditis (n = 53), autoimmune Addison's disease (n = 15), vitiligo (n = 16) and alopecia (n = 30), and 72 healthy controls - German Caucasians - to identify possible predisposing and protective HLA class II alleles in APS. In agreement with previous studies, we detected a significantly higher frequency of DR 3 and/or DR 4 in patients with APS II and III compared to controls. In patients with APS II, we detected a significantly higher frequency of DQA1*0301 and *0501 compared to controls confirming the increased frequency of an extended HLA DRB1-*04-DQA1-*03-DQB-*03 haplotype as previously described. In contrast, only DQA1*0301 was increased in our patients with APS III compared to controls. Moreover, we detected an increased frequency of DQA1*0301 in patients with APS, whereas DQA1*0301 was only significantly elevated in alopecia in patients with single-component diseases without APS. Therefore, our results indicate an association between DQA1*0301 and APS II or III since this allele was otherwise not significantly associated with any of its component diseases except alopecia. Moreover, our data imply that the allele DQA1*0301 is a marker of increased risk for further APS manifestations in patients who suffer from an organ-specific autoimmune disease.     

Increase in peripheral large granular lymphocytes in postpartum autoimmune thyroiditis

In order to elucidate the mechanism of postpartum aggravation of autoimmune thyroid disease (AITD), we serially examined the change in the proportion of peripheral large granular lymphocytes (LGL), which have activities of NK, K and/or cytotoxic T cells, in their postpartum period. Within 6 months postpartum, the percentage of LGL increased transiently in patients with AITD who remained euthyroid, or developed destructive thyrotoxicosis and/or hypothyroidism due to thyroiditis and even in normal controls. These changes in the LGL percentage were more obvious in the patients who had marked postpartum thyroid dysfunction. In contrast, we did not find a definite increase in the LGL percentage within 6 months postpartum in patients with Graves' disease who relapsed into Graves' thyrotoxicosis. These deta suggest that the increase in LGL in the postpartum period may be related to the induction of postpartum destructive thyrotoxicosis and/or hypothyroidism in AITD.     

Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases

The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).