Risk Of Graves' Disease Research Articles

Association of a CTLA-4 3′ untranslated region (CT60) single nucleotide polymorphism with autoimmune thyroid disease in the Japanese population

The etiology of the autoimmune thyroid diseases (AITDs), Graves' disease (GD) and Hashimoto's thyroiditis is largely unknown. However, genetic susceptibility is believed to play a major role. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene, encoding a negative regulator of the T-lymphocyte immune response, had been reported to be associated and/or linked to AITD. Recently, AITD susceptibility in the Caucasians was mapped to the 6.1-kb 3′UTR of the CTLA-4 gene, in which the single-nucleotide polymorphism (SNP), CT60, was most strongly associated with AITD. In order to determine the association of the CTLA-4 gene with AITD in the Japanese, case-control association analysis for the CT60 of the CTLA-4 gene using 264 AITD patients and 179 healthy controls was done. The frequency of the disease-susceptible G allele of the CT60 of the Japanese control was higher than that of the Caucasians (72.6 vs. 52.3%). However, the G allele of the CT60 was associated with GD (84.0 vs. 72.6%, P=0.0008) and AITD (80.1 vs. 72.6%, P=0.009) in the Japanese. Furthermore, the G allele of the CT60 was associated with the increased risk for GD [P=0.004, odds ratio (OR)=2.0] and AITD (P=0.03, OR=1.6) in a recessive model. These results suggested that the CTLA-4 gene is involved in the susceptibility for GD and AITD in the Japanese.

Analysis of immune regulatory genes in familial and sporadic Graves' disease.

Graves' disease (GD) is seen in apparently sporadic and familial forms. At least two immune regulatory genes are associated with GD, human leukocyte antigen (HLA) and cytotoxic T lymphocyte antigen-4 (CTLA-4). The aim of our study was to examine the contributions of HLA and CTLA-4 to the familial clustering of GD by analyzing them for association with familial and sporadic GD. We analyzed 160 Caucasian GD patients (69 familial and 91 sporadic), and 150 matched controls. Analysis of all GD patients demonstrated significant associations between GD and HLA-DR3 [P = 9.0 x 10(-7); relative risk (RR) = 3.8] and two CTLA-4 single nucleotide polymorphisms (SNPs), A/G(49) SNP (P = 0.03; RR = 1.5), and CT60 SNP (P = 0.03; RR = 1.4). Moreover, there was evidence for joint susceptibility to risk between HLA-DR3 and CTLA-4, giving a combined RR of 5.9. Subset analysis demonstrated no significant difference between the frequencies of HLA-DR3 and the susceptibility alleles of CTLA-4 A/G(49) and CT60 SNPs in the familial and sporadic GD subsets (P > 0.05). These results suggested that HLA-DR3 and CTLA-4 conferred a general increased risk for GD in both the sporadic and familial forms, and that the risk conferred by them was additive. However, HLA-DR3 and CTLA-4 did not have a stronger effect in the familial GD patients, suggesting that additional genes must contribute to the aggregation of GD within families.

Association of the T-cell regulatory gene CTLA4 with Graves' disease and autoimmune thyroid disease in the Japanese.

Autoimmune thyroid disease (AITD) is caused by an immune response to self-thyroid antigen. The cytotoxic T-lymphocyte antigen-4 ( CTLA4) gene, encoding a negative regulator of the T-lymphocyte immune response, had been reported to be associated and/or linked to AITD. Recently, AITD susceptibility in the Caucasians was mapped to the 6.1-kb 3'UTR of the CTLA4 gene, in which the three single-nucleotide polymorphisms (SNPs) CT60, JO31, and JO30 were strongly associated with AITD. In order to determine the association of the CTLA4 gene with AITD in the Japanese, case-control association analysis for the four SNPs of the CTLA4 gene using 380 AITD patients and 266 healthy controls was done. Among the SNPs examined, the SNP JO31 was most significantly associated with AITD in the Japanese, whereas the association of the JO30 with AITD was not observed. The frequency of the disease-susceptible G allele of the JO31 of the Japanese control was higher than that of the Caucasians (67.1% vs 50.2%); however, the G allele of the JO31 was associated with Graves' disease (GD) (67.1% vs 76.3%, P=0.0013) and AITD in the Japanese (67.1% vs 74.2%, P=0.0055). Furthermore, the G allele of the JO31 was associated with the increased risk for GD [ P=0.0051, odds ratio (OR)=1.7] and AITD ( P=0.016, OR=1.5) in a dominant model. These results suggested that the CTLA4 gene is involved in the susceptibility for GD and AITD in the Japanese.

Prevalence and Clinico-Epidemiology of Familial Graves' Disease in Japan based on Nationwide Epidemiologic Survey in 2001

A nationwide epidemiologic survey of familial Graves' disease (GD) was conducted in 2001. "Familial GD" was defined as a patient who had at least one Graves' patient within the proband's first-degree relatives. The primary survey was performed for estimating the prevalence of patients among a random selection of 2367 departments/hospitals of internal medicine, endocrinology, thyroidology and pediatrics. Of those receiving the primary questionnaire, 1361 (57.5%) responded, and 902 familial GD patients who visited them in 2000 were reported. The total number of patients was estimated to be 2850 (95% confidence intervals: 2100-3600). Based on the nationwide survey concerning the prevalence of hyperthyroidism in 1999, 2.1-3.1% of hyperthyroidism appeared to be familial GD and the relative risk of familial GD was roughly estimated to be 19-42. Subsequently, a second survey was carried out for obtaining the clinicoepidemiologic features of those patients. Of 902 patients, 487 (54%) were reported. No significant differences between familial and non-familial GD were found in age and sex distributions, clinical features or laboratory findings. Familial GD possessed the highest association with Hashimoto's thyroiditis, approximately 8% within the first-degree relatives, suggesting a shared genetic predisposition. These findings confirm the familial clustering of GD in the Japanese population, indicating the importance of environmental factors, genetic factors or both in the development of the disease.

A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves' disease.

Graves' disease (GD) is caused by an interplay of genetic factors and environmental triggers. The major antigen in GD is the thyrotropin receptor (TSHR) on the surface of the thyroid epithelial cell. Population-based case-control studies have largely shown no association of GD with the D36H (Asp to His) and P52T (Pro to Thr) single nucleotide polymorphisms (SNPs) in the N-terminal region of the extracellular domain of the TSHR gene in Caucasian populations. Recently, a D727E (Asp to Glu) SNP in the intracellular C-terminal domain of the TSHR was reported to be associated with GD in a Russian population. In the present study we assessed whether the codon 727 SNP is associated with GD in a Caucasian population. We found no significant differences in codon 727 SNP frequencies between GD patients and controls. In addition, our results did not show an effect of the SNP on the GD phenotype and on disease severity. Further analysis showed no evidence that the TSHR 727 SNP modulated the risk for GD conferred by HLA (DR3) and/or CTLA-4 (SNP 49 G allele) genes. A meta-analysis combining our data and those of 2 previous studies showed a very weak association between the D727E SNP and GD (p = 0.03, relative risk = 1.6). Therefore, we concluded that the TSHR gene is not a major gene for GD in our population.

Retrospective evaluation of subtotal and total thyroidectomy in Graves' disease with and without endocrine ophthalmopathy

A retrospective analysis was performed in 173 consecutive patients with Graves' disease (GD) with the principal aim of evaluating the influences of subtotal (N = 157) and total (N = 19) thyroidectomy on postoperative recurrence rates, endocrine ophthalmopathy (EO) and thyrotropin receptor antibody (TSH-R-ab) titres. Postoperatively recurrent disease, identified by increased thyroid hormone levels, occurred in 32 patients (20%) who underwent subtotal resection. These recurrences were associated with over-representation of preoperative EO (p < 0.001) as well as high TSH-R-ab levels postoperatively (p < 0.05-0.01). Subtotal and total resections were followed by an aggravation of preoperative EO in nine (16%) and one (6%), and by a development of EO in two and none of the patients, respectively. Persistently elevated TSH-R-ab titers during thyrostatic therapy became close to normalized in seven (32%) and 15 (88%) of the patients undergoing subtotal or total thyroidectomies, respectively, which illustrates a thyroid tissue dependency of the autoantibody production. Among the total material of 173 patients, altogether 75 cases exhibited persistent or progressive EO and/or TSH-R-ab elevation after more than 1 year of preoperative thyrostatic treatment. In this group, recurrent GD or aggravated EO occurred in 23 (39%) of those operated with subtotal resection and in one (6%) of those undergoing total thyroidectomy (p < 0.05). The results thus indicate that EO, particularly at the time of surgery, and prevailing TSH-R-ab titers are associated with an increased risk of recurrent GD and suggest that patients exhibiting these characteristics should benefit from total rather than subtotal thyroidectomy.