Association between thyroglobulin polymorphisms and autoimmune thyroid disease: a systematic review and meta-analysis of case-control studies.

Emerging evidence revealed that thyroglobulin (TG) contributes to the development of autoimmune disease, and the relationship between TG and autoimmune thyroid disease (AITD) is still controversial. The aim of this study was to quantify the association between rs2076740, rs853326, rs180223, and rs2069550 TG polymorphisms and risk of AITD using a meta-analysis approach. We identified all studies that assessed the association between TG polymorphisms and AITD from PubMed, Embase, and Web of Science databases. A total of 3013 cases and 1812 controls from ten case-control studies were included. There was no significant associations found between rs2069550, rs180223, and rs853326 polymorphisms and AITD risk. The association between the rs2076740 polymorphism and AITD risk was significant in the codominant model (P = 0.005), suggesting the CC rs2076740 genotype might be a protective factor for AITD. Sensitivity analysis by removing one or two study changed the results in dominant rs2076740 and rs853326 and rs2069550 allele models (P = 0.016, 0.024, 0.027). Latitude and ethnicity significantly affected the association between rs2076740 and rs2069550 polymorphisms and AITD, indicating their protective effects in allele or dominant model (P = 0.012, 0.012, 0.012, 0.009, 0.009). The association between rs2076740, rs2069550, and rs853326 polymorphisms and AITD risk is significantly affected by study characteristics.

Idiopathic Low Ovarian Reserve Is Associated with More Frequent Positive Thyroid Peroxidase Antibodies.

BACKGROUND: While screening of thyroid peroxidase antibody (TPOAb) has been recommended in women with primary ovarian insufficiency, the relationship between thyroid autoimmunity (TAI) and ovarian reserve remains undetermined. Because the TAI prevalence was reported to be different between different ethnic/racial groups, this study aimed to investigate the TAI prevalence in Chinese women with variable ovarian reserve. METHODS: This is a cross-sectional study conducted in a university infertility clinic between October 2013 and March 2016. Among patients at their first entry to the infertility clinic, a total of 1044 patients with available results of anti-Müllerian hormone (AMH), thyrotropin (TSH), TPOAb, and thyroglobulin antibody (TgAb) were enrolled. The TSH levels and the prevalence of positive TPOAb and positive TgAb were compared between patients with low, normal, and high ovarian reserve categorized with age-specific AMH levels. RESULTS: For the whole study population, the TSH levels, TPOAb positivity, and TgAb positivity were comparable between patients with variable ovarian reserve. However, after patients with known causes compromising ovarian reserve (iatrogenic or genetic) were excluded, only TPOAb positivity became significantly different between patients with low (22.7%), normal (14.0%), and high ovarian reserve (10.3%; p = 0.012). The TPOAb levels were not significantly correlated to AMH levels (Spearman's ρ = -0.027; p = 0.413). For the infertile subgroup, TPOAb positivity was significantly associated with idiopathic low ovarian reserve in unexplained infertility (low ovarian reserve: 28.6%; normal: 15.7%; high: 9.5%; p = 0.020). CONCLUSIONS: Idiopathic low ovarian reserve was associated with more frequent positive TPOAb rather than thyroid function or TgAb positivity in Chinese women.

Association of Interleukin 10 Gene Polymorphisms with Autoimmune Thyroid Disease: Meta-Analysis.

The aim of this study was to perform a meta-analysis of eligible studies and to derive a precise estimate of the association between interleukin 10 (IL10) polymorphisms and susceptibility to autoimmune thyroid disease (AITD). Meta-analyses were conducted on the associations between AITD and the -1082 G/A (rs1800896), -819 C/T (rs1800871) and -592 C/A (rs1800872) polymorphisms in IL10, and the haplotype of these polymorphisms and AITD. A total of 2903 AITD patients and 3060 controls in 10 eligible studies were included in the meta-analysis. This meta-analysis showed significant associations between IL10 at the -1082 G allele and overall AITD (OR: 1.44, 95% CI 1.13-1.82, P = 0.003), but no association between the IL10 -592 C allele and the -819 C allele and AITD. Subgroup studies demonstrated significant associations between the -1082 G allele and susceptibility to Graves' disease. Ethnicity-specific meta-analysis revealed significant associations between the -1082 G allele and AITD susceptibility in Asian populations; however, in Middle Eastern populations, no association was evident. Meta-analysis of the IL10 haplotype revealed an association between the ATA haplotype and AITD (OR: 1.17, 95% CI 1.00-1.36, P = 0.04). Meta-analysis demonstrates that the IL10 polymorphisms are associated with susceptibility to AITD.

Effect of human leukocyte antigen class II genes on Hashimoto's thyroiditis requiring replacement therapy with levothyroxine in the Japanese population.

Contribution of the human leukocyte antigen (HLA) subtype to Hashimoto's thyroiditis (HT) that requires replacement therapy with levothyroxine remains unclear in the Japanese population. The frequencies of HLA DR-DQ haplotypes were compared between patients with HT requiring levothyroxine replacement therapy and the control individuals. We studied 82 patients with HT requiring levothyroxine replacement therapy. The frequencies of DRB1*08:03-DQB1*06:01 and DRB1*09:01-DQB1*03:03 haplotypes were significantly higher in HT patients, whereas those of DRB1*13:02-DQB1*06:04 and DRB1*15:01-DQB1*06:02 haplotypes were significantly lower in these patients than in the controls. Deduced from known linkage disequilibria, DRB1*13:02-DQB1*06:04 and DRB1*15:01-DQB1*06:02 haplotypes share the same DQA1*01:02 allele. Since DQB1*06:02 and DQB1*06:04 molecules differ in the beta chain by 7 residues, these DQB1 genes are very similar. The DQA1*01:02-DQB1*06 (DQB1*06:02 or DQB1*06:04) haplotype might play a pivotal role in the resistance to HT.

Clinical and genetic characteristics of autoimmune polyglandular syndrome type 3 variant in the Japanese population.

OBJECTIVE: Type 1 diabetes (T1D) is commonly associated with autoimmune thyroid disease (AITD), and the occurrence of both T1D and AITD in a patient is defined as autoimmune polyglandular syndrome type 3 variant (APS3v). We aimed to clarify the differences in the clinical and genetic characteristics of APS3v patients and T1D patients without AITD [T1D/AITD(-)] in the Japanese population. DESIGN/PATIENTS: Our subjects were 54 APS3v patients and 143 T1D/AITD(-) patients who were consecutively diagnosed at Nagasaki University Hospital from 1983 to the present. RESULTS: A remarkable female predominance, a slow and older age onset of T1D, and a higher prevalence of glutamic acid decarboxylase autoantibodies were observed in APS3v patients compared to T1D/AITD(-) patients. The older onset age of T1D in APS3v patients was associated with a higher proportion of slow-onset T1D. Among the two major susceptible human leukocyte antigen (HLA) class II haplotypes in Japanese T1D, DRB1*0405-DQB1*0401, but not DRB1*0901-DQB1*0303, was associated with APS3v patients. Furthermore, DRB1*0803-DQB1*0601 was not protective in patients with APS3v. The frequencies of the GG genotype in +49G>A and +6230G>A polymorphism in the CTLA4 gene were significantly higher in T1D/AITD(-) patients, but not in APS3v patients, compared to control subjects. CONCLUSIONS: In conclusion, we found notable differences in the clinical and genetic characteristics of APS3v patients and T1D/AITD(-) patients in the Japanese population, and the differences in the clinical characteristics between the two groups may reflect distinct genetic backgrounds including the HLA DRB1-DQB1 haplotypes and CTLA4 gene polymorphisms.

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

OBJECTIVE: To 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 antibody-negative groups. METHODS: In 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. RESULTS: The 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. CONCLUSION: Our 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.

Association of HLA alleles with autoimmune thyroid disease in Korean children.

BACKGROUNDS: Data regarding genetics of Hashimoto's disease (HD) and Graves' disease (GD) in Korean children are lacking. METHODS: 73 patients with autoimmune thyroid disease (AITD; HD 32, GD 41) were recruited. We analyzed human leukocyte antigen (HLA) class I and HLA-DRB1 by PCR-SSP, and compared them with those of 159 controls. RESULTS: In AITD, the allele frequencies of HLA-A*02, -B*46, -Cw*01 and -DRB1*08 were higher and those of HLA-A*30, -B*07, -Cw*07 and -DRB1*01 were lower than in controls. In HD, those of HLA-B*46 and -Cw*01 were higher and those of HLA-DRB1*01 and -Cw*07 were lower than in controls. In GD, those of HLA-A*02, -B*46, -Cw*01 and -DRB1*08 were higher and those of HLA-DRB1*07 and -Cw*07 were lower than in controls. Between HD and GD, there were no significant differences in allele frequencies. The risk of AITD in the presence of both HLA-B*46 and -Cw*01 is higher than in the presence of either allele alone. CONCLUSION: The susceptible and protectable alleles in HD are similar to those in GD. Coexistence of HLA-B*46 and -Cw*01 may be a genetic gene marker for early-onset AITD in Koreans.

Epitope analysis of GAD65 autoantibodies in adult-onset type 1 diabetes and latent autoimmune diabetes in adults with thyroid autoimmunity.

This study aimed at determining which GAD65 epitopes the spontaneous antibodies recognized and whether the epitope-specific GAD65Abs could be associated with the development of thyroid autoimmunity in Chinese adult-onset type 1 diabetes (T1DM) and latent autoimmune diabetes in adults (LADA). The levels of GAD65Abs and their reactivities to N-terminal (GAD65-N), middle (GAD65-M) and C-terminal (GAD65-C) regions of human GAD65 were measured by radioligand assay in 109 patients with adult-onset T1DM and 107 with LADA. TPOAb, TGAb and the genotypes of HLADQA1-DQB1 were determined. The percentage of LADA patients with GAD65-NAb was significantly higher than that of adult-onset T1DM patients (21.5% vs. 11.0%, P = 0.037), but LADA patients with GAD65-CAb less than T1DM patients (47.7% vs. 70.6%, P = 0.001). LADA patients with both GAD65-M and GAD65-CAb (GAD65-M + CAb) appeared to be at higher risk for the development of thyroid autoimmunity, lower serum C-peptide level and the requirement for insulin therapy (P < 0.05). More frequent T1DM patients with HLADQA1*03-DQB1*0303 developed GAD65-M + CAb (55.8% vs. 35.1%, P = 0.008). In comparison with those without thyroid autoimmunity, more frequent T1DM patients and LADA patients with thyroid autoimmunity displayed GAD65-M + CAbs (44.0% vs.16.9% and 53.1% vs. 17.3%, P = 0.002 and <0.001, respectively) with a diagnostic specificity of 83.1 or 82.7% for thyroid autoimmunity, respectively. LADA patients with GAD65-M + CAbs had clinical features similar to T1DM patients. Adult-onset T1DM and LADA patients with GAD65-M + CAbs are at an increased risk for the development of thyroid autoimmunity.

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

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by interplays of genetic factors and environmental triggers. Interleukin-23 and its receptor (IL-23R) guide T cells towards the Th17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis, and Graves' ophthalmopathy (GO) in Caucasians. To determine whether variants in the IL-23R gene are associated with AITDs in Japanese, 464 Japanese AITD patients (290 with GD, 174 with HT) and 179 matched Japanese control subjects were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using TaqMan allelic discrimination assays and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. Case-control association studies were performed using the chi(2) and Fisher's exact tests with Yates correction. Of the four SNPs rs11209026 was non-polymorphic in our dataset. The other three SNPs were not associated with GD or GO or HT in our Japanese population. These results suggest that the IL-23R gene is associated with AITDs only in a specific ethnic group.

The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts.

FOXP3 is a key gene in the development of regulatory T cells (Treg). FOXP3 expression commits naïve T cells to become Treg cells. Indeed, mutations in the FOXP3 gene cause severe systemic autoimmune diseases in humans and in mice. Therefore, we hypothesized that the FOXP3 gene may be associated with thyroid autoimmunity which is among the typical autoimmune diseases that develop in individuals with FOXP3 mutations. Moreover, the FOXP3 gene is located within an X-chromosome locus (Xp11.23) previously shown to be linked with autoimmune thyroid diseases (AITD). We tested the FOXP3 gene locus for association with AITD in two large cohorts of US Caucasians and Japanese AITD patients. We analyzed 269 Caucasian AITD patients (52 males and 217 females) and 357 Caucasian controls (159 males and 198 females), as well as 377 female Japanese AITD patients and 179 female Japanese controls. The FOXP3 gene locus was analyzed using four microsatellite polymorphisms [(GT)n; (TC)n; DXS573; DXS1208] flanking the FOXP3 gene locus. Interestingly, while no association was found between FOXP3 polymorphisms and AITD in the Japanese cohort there was a significant association in the Caucasian cohort. There was a significant association of the (TC)n polymorphism with AITD in the Caucasian male AITD patients (p=0.011; 5 degrees of freedom [df]). Similarly, there was an association between the DXS573 microsatellite and AITD in the Caucasian female AITD patients (p=0.00023; 4 df). These results suggest that polymorphisms of the FOXP3 gene may play a role in the genetic susceptibility to AITD in Caucasians, perhaps by altering FOXP3 function and/or expression.

Resistance to thyroid hormone associated with autoimmune thyroid disease in a Turkish family.

The syndrome of resistance to thyroid hormone (RTH) is characterized by impaired tissue responses to thyroid hormone. Hashimoto's thyroiditis is the most common thyroid autoimmune disease. We present a Turkish family with both RTH and Hashimoto's thyroiditis. RTH was detected through the presence of point mutation in thyroid hormone receptor (TR), and Hashimoto's thyroiditis was diagnosed due to the presence of thyroid autoantibodies. The proposita, her affected mother as well as her unaffected sister have thyroid autoantibodies consistent with Hashimoto's thyroiditis, and a heterozygous point mutation in exon 10 encoding the ligand (3,3',5-L-T3)-binding domain of the TRbeta gene was detected in both the proposita and the mother. The mutation is a replacement of cytosine for guanine in codon 453 (CCT->GCT) producing a missense mutation substituting a normal proline with an alanine (P453A), which reduces the affinity for T3 to 17% of that of the normal TRbeta. Both also have modest elevation of serum TSH levels. In severe RTH, marked elevation of thyroid hormone concentrations in the absence of suppressed TSH supports the laboratory diagnosis of RTH. However, when RTH is mild and associated with thyroiditis, even a modest thyroid gland insufficiency can obliterate the serum T4 and T3 elevations, typical of RTH. This will manifest as elevated serum TSH. Demonstration of TRbeta gene mutation is then necessary to establish the diagnosis. In addition, under these circumstances, treatment with thyroid hormone should be considered.

HLA haplotypes associated with type 1 diabetes mellitus in North Indian children.

Human leukocyte antigen (HLA) encoded susceptibility to develop type 1 diabetes mellitus (T1DM) has been investigated in children from North India. The results revealed significantly increased prevalence of HLA-A26, -B8, and -B50 among patients and strong positive association of the disease with DRB1*0301 (82.1% vs 13.9%, chi2=71.3, odds ratio [OR]=28.3) and a negative association with DRB1*02 (chi2=12.2, PF=38.5). HLA-DQB1*0201 occurred in 96.4% of the patients, whereas the heterodimer DQA1*0501-DQB1*0201 was present in 82.1% of patients (60.7% in single dose and 21.4% in double dose) and revealed significant deviation from the healthy controls (chi2=74.1, pc=6.0E-10). In addition to DRB1*03, positive association was also observed with DRB1*09 (14.3% vs 1.3%, chi2=13.4) and DRB1*04 (39.3% vs 15.6%, chi2=8.39). No HLA association was observed in relation to residual pancreatic beta-cell function or associated thyroid autoimmunity. Family analysis revealed involvement of multiple DR3+ve haplotypes with T1DM in North Indian children with A26-B8-DRB1*03 (25% vs 3.5%, chi2=16.9, p=3.96E-05) and Ax-B50-DRB1*03 (25% vs 0.7%, chi2=44.7, p=9.88E-11) being the most frequent haplotypes encountered among patients. The classical Caucasian haplotype A1-B8-DRB1*03 was infrequent (7.2%) among the diabetic children. The study highlights the race specificity of HLA association and disease associated HLA haplotypes in T1DM among North Indian children.

The contribution of immune regulatory and thyroid specific genes to the etiology of Graves' and Hashimoto's diseases.

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) are believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely these loci interact and their interactions may influence disease phenotype and severity.

Autoimmune thyroid disease susceptibility loci in a large Chinese family.

OBJECTIVES: The autoimmune thyroid diseases (AITDs) comprising Graves' disease (GD) and Hashimoto's thyroiditis (HT) are complex genetic diseases, which result from an interaction between predisposing genes and environmental triggers. The aim of our study was to dissect the genetic predisposition to GD and HT in one large Chinese family with multiple members affected with AITD. PATIENTS: We completed a whole genome screen of a large multiplex Chinese-American family. We enrolled 27 family members from three generations. Eight members were affected with AITD, six had GD and two had HT. DESIGN: We determined the information limits of the family. Power calculations indicated that the maximum attainable LOD scores were 5.1 assuming dominant inheritance, and 3.4 assuming recessive inheritance. These estimates both assumed 100% penetrance and one gene. Whole genome screening was performed using 400 highly polymorphic and densely spaced microsatellite markers spanning the entire human genome (intermarker distance < 10 cM). Linkage analysis was performed using two-point and multipoint parametric and nonparametric methods. RESULTS: Initial whole genome screening performed with 400 microsatellite markers identified two markers that showed evidence for linkage to AITD in this family, D11S4191 and D9S175, with two-point LOD scores of 2.31 and 2.05, respectively. Multipoint linkage analysis focusing on the regions containing these markers revealed a maximum multipoint LOD score (MLS) of 2.13 and a nonparametric linkage score (NPL) of 6.1 for D11S4191 and an MLS of 2.01 and NPL of 7.5 for D9S175. CONCLUSIONS: These results showed that this Chinese family harboured susceptibility loci for AITD which were distinct from those previously found in the Caucasian population. This suggests that different susceptibility loci exist between different ethnic groups. Furthermore, even within a single family from a genetically homogenous population, more than one gene was involved in the genetic susceptibility to AITD, supporting the notion that AITDs are caused by multiple genes of varying influences.

Optic-spinal form of multiple sclerosis and anti-thyroid autoantibodies.

The optic-spinal form of multiple sclerosis (OSMS), characterized by recurrent involvement of optic nerve and spinal cord with rare brain magnetic resonance imaging lesions, is relatively common among Asians. While individual cases of OSMS with anti-thyroid autoantibodies (ATABs) have been reported, the frequency of ATAbs in OSMS and classical multiple sclerosis has not been studied. We studied serum ATAbs and anti-nuclear antibodies (ANA) in 46 Japanese patients with multiple sclerosis: 14 with OSMS, and 32 with non-OSMS. Six patients were positive for ATAbs: five women with OSMS and one man with non-OSMS. The frequency of ATAbs in OSMS (5/14) was significantly higher than that in non-OSMS (1/32; P = 0.007), but the frequency of ANA did not differ between OSMS (3/14) and non-OSMS (6/32; P = 0.99). There may be a pathogenetic link between anti-thyroid autoimmunity and a subgroup of OSMS in Japanese.

Racial and age-related differences in incidence and severity of focal autoimmune thyroiditis.

To determine possible racial and age-related differences of focal autoimmune thyroiditis between white and black Americans, autopsy material from American subjects was evaluated for incidence and severity of chronic lymphocytic thyroiditis. The overall incidence of lymphocytic infiltration in thyroid sections from subjects aged more than 20 years was 41.4% in white females, 20% in white males, 17.4% in black females, and 8.5% in black males. An increase to 54.8% in incidence of thyroiditis from the first decade onward was noted in white females older than 80 years of age. Age did not cause a remarkable increase in incidence of thyroiditis in white males, in black females, or black males. The susceptibility to chronic thyroiditis in American white males and females was almost the same as that of British white males and females. The incidence of thyroiditis in black females and males was similar to that in Japanese females and males. These findings showed clear racial differences in susceptibility to chronic thyroiditis.

Is focal chronic autoimmune thyroiditis an age-related disease? Differences in incidence and severity between Japanese and British.

The incidence of chronic lymphocytic thyroiditis in autopsy material from Japanese and British subjects was evaluated. Lymphocytic infiltration in representative thyroid sections from 1826 Japanese cases collected from four different institutions was analysed. The overall incidence of lymphocytic infiltration was significantly higher in females (22.2 per cent) than in males (13.9 per cent). In females, the incidence reached 23.2 per cent in the fourth decade and showed no increase with age thereafter. The overall incidence of lymphocytic infiltration in thyroid sections from 810 British cases was 42.5 per cent in females and 19.4 per cent in males; an increase in the incidence of thyroiditis from the sixth decade onwards was noted in British females, the figure reaching 50.0 per cent in those aged over 70 years. These findings suggest possible racial differences in susceptibility to chronic thyroiditis. The disorder is not necessarily related to age, increasing severity of disease with age being found only in British females.

Strong association between HLA DRw9 and Hashimoto's thyroiditis in southern Chinese.

The distribution of HLA-A, -B, and -DR antigens in 53 Southern Chinese patients with Hashimoto's thyroiditis including 33 with goitre and 20 without goitre was compared with the distribution in 100 Southern Chinese controls. There was a significantly increased prevalence of HLA Bw46 in the nongoiterous patients and of HLA DRw9 in both groups of patients, but only for HLA DRw9 in the goiterous group was the increase significant after adjustment for the number of antigens studied. Based on these findings and those in other autoimmune diseases it is considered that the haplotype Bw46, DRw9 in Chinese takes the place of B8, DR3 in Caucasians in carrying genes which predispose to the development of auto-immune disease.