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Klaus Badenhoop - One of the best experts on this subject based on the ideXlab platform.
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fas ligand gene polymorphisms are not associated with hashimoto s thyroiditis and Graves Disease
Human Immunology, 2003Co-Authors: Bettina J Stuck, K. H. Usadel, Michael A Pani, Foued Besrour, Maria Segni, Maren Krause, Klaus BadenhoopAbstract:Hashimoto's thyroiditis and Graves' Disease represent the two most common autoimmune thyroid disorders. Whereas in Hashimoto's thyroiditis FasL expression causes thyrocytes to undergo apoptosis, additional anti-apoptotic molecules appear to protect these cells in Graves' Disease. Mutations of the FasL gene were observed in systemic lupus erythematosus. Given its functional relevance for the pathogenesis of thyroid autoimmunity we wondered whether variants of the FasL gene play a role in Hashimoto's thyroiditis and Graves' Disease. We genotyped families with at least one offspring affected by Hashimoto's thyroiditis (n = 86) and Graves' Disease (n = 90) for two FasL gene polymorphisms (C -843 T in the promoter, A IVS2nt-124 G in intron 2). Extended transmission disequilibrium (ETDT) and chi(2) testing were performed. Neither polymorphism alone nor the promoter/intron 2 haplotypes (p = 0.91) were associated with Hashimoto's thyroiditis. No association with Graves' Disease was observed for the promoter polymorphism (p = 0.91) and the intron 2 "A" allele (57.1%; p = 0.36) or the promoter/intron 2 haplotypes (p = 0.31). Moreover, intron 2 genotyping revealed no difference between an additional 251 patients with Graves' Disease and 197 healthy controls (p = 0.37). Italian and German families did not differ for the studied polymorphisms. In conclusion, our data do not suggest common genetic FasL variants to significantly contribute to the pathogenesis of either Hashimoto's thyroiditis or Graves' Disease.
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second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves Disease
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Sabine Costagliola, Klaus Badenhoop, Nils G Morgenthaler, Rudolf Hoermann, Joachim Struck, Dirk Freitag, Stefan Poertl, Wolfgang Weglohner, Jorg M Hollidt, B QuadbeckAbstract:Detection of autoantibodies to the TSH receptor (TSH-R) in Graves' Disease has found widespread use in clinical routine and is performed mostly by commercial RRAs measuring TSH binding inhibitory activity. We report in this study on a second generation TSH binding inhibitory assay using the human recombinant TSH-R with two major improvements: 1) superior diagnostic sensitivity for Graves' Disease, and 2) for the first time, nonradioactive and radioactive coated tube (CT) technology. Full-length human recombinant TSH-R was expressed in the K562 leukemia cell line and grown in suspension at a high density. A murine monoclonal antibody was selected for binding to the native TSH-R without interfering with autoantibodies or TSH and was coated to polystyrene tubes. After detergent extraction, TSH-R was affinity immobilized on antibody-coated tubes. The binding of TSH to the TSH-R could be demonstrated by the addition of 125I- or acridinium ester-labeled bovine TSH, and this binding could be inhibited by sera from patients with Graves' Disease up to 95%. Subsequently, these novel assays, a CT RRA and a CT luminescence receptor assay, were compared to the conventional RRA based on porcine antigen in a blinded clinical multicenter trial. Sera from 328 patients with Graves' Disease (86 untreated, 116 treated, and 126 in remission) and 520 controls (comprised of healthy blood donors and patients with autoimmune Diseases or goiter) were tested in all 3 assays. Receiver-operating characteristic plot analysis resulted in a specificity of 99.6% with a sensitivity of 98.8% for both CT assays, compared to 99.6% specificity and 80.2% sensitivity for the conventional RRA (P < 0.001). In all 3 groups of patients with Graves' Disease, the 2 CT assays were significantly more sensitive for the Disease than the conventional assay, without loss of specificity in the control groups. This increase in sensitivity and the nonradioactive or radioactive CT format constitute a significant improvement over the currently available assays.
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POLYMORPHISMS OF TAP1 AND TAP2 GENES IN Graves' Disease
Tissue antigens, 1997Co-Authors: H. Rau, A. Nicolay, K. H. Usadel, R. Finke, Horst Donner, Paul G. Walfish, Klaus BadenhoopAbstract:Graves' Disease is an autoimmune disorder in which HLA DQA1*0501 and DQB1*0201 confer predisposition. The genes for transporters associated with antigen processing (TAP1 and TAP2) locate near to HLA DQ coding regions and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to Graves' Disease by a possibly different selection of antigenic peptides, we investigated sequence variants of TAP1 and TAP2 genes in 235 patients with Graves' Disease and 218 random healthy controls by polymerase chain reaction (PCR) followed by sequence specific oligonucleotide analysis (SSO), single strand conformational polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*0301 (Val-333/Asp-637: 71% vs. 55% in controls, p < 0.008, RR = 2.05) and TAP2*0101 (Val-379/Ala-565/Thr-665/stop-687: 83% vs. 69% in controls, p < 0.03, RR = 2.20) showed a positive association with Graves' Disease whereas TAP1*0401 a negative (Ile-333/Gly-637: 4% vs. 13% in controls, p < 0.01, RR = 0.25). After selection of patients and controls for HLA DQA1*0501 a similar association was found for TAP1*0301 (72% vs. 50% in controls, p < 0.02, RR = 2.63) and TAP1*0401 (4% vs. 16% in controls, p < 0.04, RR = 0.22), when matching for HLA DQB1*0201 as well as for TAP1*0401 (3% vs. 16% in controls, p < 0.05, RR = 0.18). Our findings indicate that the positive association of TAP1*0301 and the negative of TAP1*0401 with Graves' Disease cannot only be explained by linkage disequilibrium between TAP alleles and HLA DQ. Therefore, these TAP alleles contribute to genetic susceptibility in Graves' Disease as additional permissive and protective factors.
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ctla4 alanine 17 confers genetic susceptibility to Graves Disease and to type 1 diabetes mellitus
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: Horst Donner, K. H. Usadel, R. Finke, Paul G. Walfish, J Braun, T Siegmund, J Herwig, Klaus BadenhoopAbstract:The genetic susceptibility to Graves’ Disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine Disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves’ Disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves’ Disease, 293 patients with IDDM, and 325 controls. Patients with Graves’ Disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 × 10−4). The phenotypic f...
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ctla4 alanine 17 confers genetic susceptibility to Graves Disease and to type 1 diabetes mellitus
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: Horst Donner, H. Rau, K. H. Usadel, R. Finke, Paul G. Walfish, J Braun, T Siegmund, J Herwig, Klaus BadenhoopAbstract:The genetic susceptibility to Graves' Disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine Disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' Disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' Disease, 293 patients with IDDM, and 325 controls. Patients with Graves' Disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' Disease as well as to IDDM.
Rebecca S Sippel - One of the best experts on this subject based on the ideXlab platform.
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clinical and socioeconomic factors influence treatment decisions in Graves Disease
Annals of Surgical Oncology, 2015Co-Authors: Dawn M Elfenbein, Herbert Chen, David F Schneider, Jeffrey A Havlena, Rebecca S SippelAbstract:Definitive treatment of Graves’ Disease includes radioactive iodine (RAI) and thyroidectomy, but utilization varies. We hypothesize that, in addition to clinical reasons, there are socioeconomic factors that influence whether a patient undergoes thyroidectomy or RAI. Patients treated for Graves’ Disease between August 2007 and September 2013 at our university hospital were included. A comparative analysis of clinical and socioeconomic factors was completed. Of 427 patients, 300 (70 %) underwent RAI, whereas 127 (30 %) underwent surgery. Multiple factors were associated with surgery: younger age (mean 36 vs. 41 years, p < 0.01), female gender (33 vs. 19 % males, p = 0.01), black race (56 vs. 28 % nonblack, p < 0.01), Medicaid or uninsured (43 vs. 27 % private insurance or Medicare, p < 0.01), ophthalmopathy (38 vs. 26 %, p < 0.01), goiter (35 vs. 23 %, p < 0.01), and lowest quartile of median household income (38 vs. 27 % upper three quartiles, p = 0.03). Thyroidectomy increased annually, with 52 % undergoing surgery during the final year (p < 0.01). Adjusting for confounding, younger age (odds ratio [OR] 1.04; 95 % confidence interval [CI] 1.02, 1.05), female gender (OR 2.06; 95 % CI 1.06, 4.01), ophthalmopathy (OR 2.35; 95 % CI 1.40, 3.96), and later year of treatment (OR 1.66; 95 % CI 1.41, 1.95) remained significantly associated with surgery. Surgery has now become the primary treatment modality of choice for Graves’ Disease at our institution. Clinical factors are the main drivers behind treatment choice, but patients with lower SES are more likely to have clinical features best treated with surgery, underlying the importance of improving access to quality surgical care for all patients.
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preventing postoperative hypocalcemia in patients with Graves Disease a prospective study
Annals of Surgical Oncology, 2015Co-Authors: Sarah C Oltmann, Herbert Chen, Sarah Schaefer, David F Schneider, Andrew V Brekke, Rebecca S SippelAbstract:Background Hypocalcemia occurs after total thyroidectomy (TT) for Graves Disease via parathyroid injury and/or from increased bone turnover. Current management is to supplement calcium after surgery. This study evaluates the impact of preoperative calcium supplementation on hypocalcemia after Graves TT.
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total thyroidectomy a safe and effective treatment for Graves Disease
Journal of Surgical Research, 2009Co-Authors: Jing Liu, Herbert Chen, Anna Bargren, Sarah Schaefer, Rebecca S SippelAbstract:Background Thyroidectomy as a first line treatment for Graves’ Disease is rarely utilized in the US. The purpose of this study was to analyze the safety and efficacy of thyroid surgery among patients with Graves’ Disease. Methods Fifty-six patients with Graves’ Disease underwent thyroid surgery between May 1994 and May 2008 at a single academic institution. Preoperative, intraoperative, and postoperative variables were analyzed. Results A total of 58 surgeries were performed: 55.1% (n = 32) total thyroidectomy, 41.3% (n = 24) subtotal/lobectomy, 3.4% (n = 2) completion thyroidectomy. The average gland weight was 47.3 ± 10.8 gm, with 70% weighing > 30 gm. Reasons for having thyroid surgery were persistent Disease despite medical therapy (46.6%), patient preference (24.1%), multinodular goiter/cold nodules (20.3%), failed RAI (radioactive iodine) treatment (16%), and opthalmopathy (12.1%). Of those patients that failed prior RAI therapy, the only factor that was predictive of failure was Disease severity, as demonstrated by a markedly elevated initial free-T4 value (11.8 ± 4.5 ng/dL, P = 0.04). Transient symptomatic hypocalcemia occurred in 10.7% (n = 6) of patients, and one patient (1.8%) had symptomatic hypocalcemia lasting > 6 mo. There were no permanent recurrent laryngeal nerve injuries. There was no difference in overall complication rates between patients based on surgical procedure (subtotal versus total thyroidectomy), preoperative RAI treatment, or gland size. Recurrences occurred in 6% of the subtotal thyroidectomy group and 0% of the total thyroidectomy group (P = 0.008). Conclusion Thyroidectomy for patients with Graves’ Disease can be performed with very low complication rates and when a total thyroidectomy is performed, there is almost no risk of recurrence.
Herbert Chen - One of the best experts on this subject based on the ideXlab platform.
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clinical and socioeconomic factors influence treatment decisions in Graves Disease
Annals of Surgical Oncology, 2015Co-Authors: Dawn M Elfenbein, Herbert Chen, David F Schneider, Jeffrey A Havlena, Rebecca S SippelAbstract:Definitive treatment of Graves’ Disease includes radioactive iodine (RAI) and thyroidectomy, but utilization varies. We hypothesize that, in addition to clinical reasons, there are socioeconomic factors that influence whether a patient undergoes thyroidectomy or RAI. Patients treated for Graves’ Disease between August 2007 and September 2013 at our university hospital were included. A comparative analysis of clinical and socioeconomic factors was completed. Of 427 patients, 300 (70 %) underwent RAI, whereas 127 (30 %) underwent surgery. Multiple factors were associated with surgery: younger age (mean 36 vs. 41 years, p < 0.01), female gender (33 vs. 19 % males, p = 0.01), black race (56 vs. 28 % nonblack, p < 0.01), Medicaid or uninsured (43 vs. 27 % private insurance or Medicare, p < 0.01), ophthalmopathy (38 vs. 26 %, p < 0.01), goiter (35 vs. 23 %, p < 0.01), and lowest quartile of median household income (38 vs. 27 % upper three quartiles, p = 0.03). Thyroidectomy increased annually, with 52 % undergoing surgery during the final year (p < 0.01). Adjusting for confounding, younger age (odds ratio [OR] 1.04; 95 % confidence interval [CI] 1.02, 1.05), female gender (OR 2.06; 95 % CI 1.06, 4.01), ophthalmopathy (OR 2.35; 95 % CI 1.40, 3.96), and later year of treatment (OR 1.66; 95 % CI 1.41, 1.95) remained significantly associated with surgery. Surgery has now become the primary treatment modality of choice for Graves’ Disease at our institution. Clinical factors are the main drivers behind treatment choice, but patients with lower SES are more likely to have clinical features best treated with surgery, underlying the importance of improving access to quality surgical care for all patients.
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preventing postoperative hypocalcemia in patients with Graves Disease a prospective study
Annals of Surgical Oncology, 2015Co-Authors: Sarah C Oltmann, Herbert Chen, Sarah Schaefer, David F Schneider, Andrew V Brekke, Rebecca S SippelAbstract:Background Hypocalcemia occurs after total thyroidectomy (TT) for Graves Disease via parathyroid injury and/or from increased bone turnover. Current management is to supplement calcium after surgery. This study evaluates the impact of preoperative calcium supplementation on hypocalcemia after Graves TT.
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total thyroidectomy a safe and effective treatment for Graves Disease
Journal of Surgical Research, 2009Co-Authors: Jing Liu, Herbert Chen, Anna Bargren, Sarah Schaefer, Rebecca S SippelAbstract:Background Thyroidectomy as a first line treatment for Graves’ Disease is rarely utilized in the US. The purpose of this study was to analyze the safety and efficacy of thyroid surgery among patients with Graves’ Disease. Methods Fifty-six patients with Graves’ Disease underwent thyroid surgery between May 1994 and May 2008 at a single academic institution. Preoperative, intraoperative, and postoperative variables were analyzed. Results A total of 58 surgeries were performed: 55.1% (n = 32) total thyroidectomy, 41.3% (n = 24) subtotal/lobectomy, 3.4% (n = 2) completion thyroidectomy. The average gland weight was 47.3 ± 10.8 gm, with 70% weighing > 30 gm. Reasons for having thyroid surgery were persistent Disease despite medical therapy (46.6%), patient preference (24.1%), multinodular goiter/cold nodules (20.3%), failed RAI (radioactive iodine) treatment (16%), and opthalmopathy (12.1%). Of those patients that failed prior RAI therapy, the only factor that was predictive of failure was Disease severity, as demonstrated by a markedly elevated initial free-T4 value (11.8 ± 4.5 ng/dL, P = 0.04). Transient symptomatic hypocalcemia occurred in 10.7% (n = 6) of patients, and one patient (1.8%) had symptomatic hypocalcemia lasting > 6 mo. There were no permanent recurrent laryngeal nerve injuries. There was no difference in overall complication rates between patients based on surgical procedure (subtotal versus total thyroidectomy), preoperative RAI treatment, or gland size. Recurrences occurred in 6% of the subtotal thyroidectomy group and 0% of the total thyroidectomy group (P = 0.008). Conclusion Thyroidectomy for patients with Graves’ Disease can be performed with very low complication rates and when a total thyroidectomy is performed, there is almost no risk of recurrence.
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the surgical management of Graves Disease
Journal of Surgical Research, 2006Co-Authors: Chris M Schusslerfiorenza, Cristin M Bruns, Herbert ChenAbstract:Background The historical aspects of the pathophysiology and treatment of Graves’ Disease are briefly discussed in this paper. Materials and methods The three treatment modalities of Graves’ Disease are anti-thyroid drug therapy, radioactive iodine therapy, and surgery. Although the majority of patients with Graves’ Disease in the U.S. are treated with radioactive iodine, surgery still plays an important role when patients cannot tolerate anti-thyroid drug therapy, when medical treatment is rejected by patients, or when surgery is deemed the fastest and safest route in managing the patient. Conclusions The indications for surgical management of Graves’ Disease are discussed with emphasis on available data supporting the extent of thyroid resection based on the incidences of hypothyroidism, recurrence of hyperthyroidism, recurrent laryngeal nerve injury and hypoparathyroidism.
Bong-yun Cha - One of the best experts on this subject based on the ideXlab platform.
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Refractory Graves ’ Disease Successfully Cured by Adjunctive Cholestyramine and Subsequent Total
2016Co-Authors: Endocrinol Metab, Yeoree Yang, Seawon Hwang, Minji Kim, Yejee Lim, Min-hee Kim, Sohee Lee, Dong-jun Lim, Moo-il Kang, Bong-yun ChaAbstract:The three major forms of treatment for Graves thyrotoxicosis are antithyroid drugs, radioactive iodine therapy and thyroidectomy. Surgery is the definitive treatment for Graves thyrotoxicosis that is generally recommended when other treatments have failed or are contraindicated. Generally, thyrotoxic patients should be euthyroid before surgery to minimize potential complications which usually requires preoperative management with thionamides or inorganic iodine. But several cases of refractory Graves ’ Disease have shown resistance to conventional treatment. Here we report a 40-year-old female patient with Graves ’ Disease who com-plained of thyrotoxic symptoms for 7 months. Her thyroid function test and thyroid autoantibody profiles were consistent with Graves ’ Disease. One kind of thionamides and β-blocker were started to control her Disease. However, she was resistant to nearly all conventional medical therapies, including β-blockers, inorganic iodine, and two thionamides. She experienced hepatotoxicity from the thionamides. What was worse is her past history of serious allergic reaction to corticosteroids, which are often used to help control symptoms. A 2-week regimen of high-dose cholestyramine improved her uncontrolled thyrotoxicosis and subsequent thyroidectomy was successfully performed. In conclusion, cholestyramine could be administered as an effective and safe adjunc-tive agent for preoperative preparation in patients with severe hyperthyroid Graves ’ Disease that is resistant to conventional thera-pies
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refractory Graves Disease successfully cured by adjunctive cholestyramine and subsequent total thyroidectomy
Endocrinology and Metabolism, 2015Co-Authors: Yeoree Yang, Seawon Hwang, Minji Kim, Yejee Lim, Min-hee Kim, Sohee Lee, Dong-jun Lim, Moo-il Kang, Bong-yun ChaAbstract:The three major forms of treatment for Graves thyrotoxicosis are antithyroid drugs, radioactive iodine therapy and thyroidectomy. Surgery is the definitive treatment for Graves thyrotoxicosis that is generally recommended when other treatments have failed or are contraindicated. Generally, thyrotoxic patients should be euthyroid before surgery to minimize potential complications which usually requires preoperative management with thionamides or inorganic iodine. But several cases of refractory Graves' Disease have shown resistance to conventional treatment. Here we report a 40-year-old female patient with Graves' Disease who complained of thyrotoxic symptoms for 7 months. Her thyroid function test and thyroid autoantibody profiles were consistent with Graves' Disease. One kind of thionamides and β-blocker were started to control her Disease. However, she was resistant to nearly all conventional medical therapies, including β-blockers, inorganic iodine, and two thionamides. She experienced hepatotoxicity from the thionamides. What was worse is her past history of serious allergic reaction to corticosteroids, which are often used to help control symptoms. A 2-week regimen of high-dose cholestyramine improved her uncontrolled thyrotoxicosis and subsequent thyroidectomy was successfully performed. In conclusion, cholestyramine could be administered as an effective and safe adjunctive agent for preoperative preparation in patients with severe hyperthyroid Graves's Disease that is resistant to conventional therapies.
Horst Donner - One of the best experts on this subject based on the ideXlab platform.
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POLYMORPHISMS OF TAP1 AND TAP2 GENES IN Graves' Disease
Tissue antigens, 1997Co-Authors: H. Rau, A. Nicolay, K. H. Usadel, R. Finke, Horst Donner, Paul G. Walfish, Klaus BadenhoopAbstract:Graves' Disease is an autoimmune disorder in which HLA DQA1*0501 and DQB1*0201 confer predisposition. The genes for transporters associated with antigen processing (TAP1 and TAP2) locate near to HLA DQ coding regions and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to Graves' Disease by a possibly different selection of antigenic peptides, we investigated sequence variants of TAP1 and TAP2 genes in 235 patients with Graves' Disease and 218 random healthy controls by polymerase chain reaction (PCR) followed by sequence specific oligonucleotide analysis (SSO), single strand conformational polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*0301 (Val-333/Asp-637: 71% vs. 55% in controls, p < 0.008, RR = 2.05) and TAP2*0101 (Val-379/Ala-565/Thr-665/stop-687: 83% vs. 69% in controls, p < 0.03, RR = 2.20) showed a positive association with Graves' Disease whereas TAP1*0401 a negative (Ile-333/Gly-637: 4% vs. 13% in controls, p < 0.01, RR = 0.25). After selection of patients and controls for HLA DQA1*0501 a similar association was found for TAP1*0301 (72% vs. 50% in controls, p < 0.02, RR = 2.63) and TAP1*0401 (4% vs. 16% in controls, p < 0.04, RR = 0.22), when matching for HLA DQB1*0201 as well as for TAP1*0401 (3% vs. 16% in controls, p < 0.05, RR = 0.18). Our findings indicate that the positive association of TAP1*0301 and the negative of TAP1*0401 with Graves' Disease cannot only be explained by linkage disequilibrium between TAP alleles and HLA DQ. Therefore, these TAP alleles contribute to genetic susceptibility in Graves' Disease as additional permissive and protective factors.
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ctla4 alanine 17 confers genetic susceptibility to Graves Disease and to type 1 diabetes mellitus
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: Horst Donner, K. H. Usadel, R. Finke, Paul G. Walfish, J Braun, T Siegmund, J Herwig, Klaus BadenhoopAbstract:The genetic susceptibility to Graves’ Disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine Disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves’ Disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves’ Disease, 293 patients with IDDM, and 325 controls. Patients with Graves’ Disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 × 10−4). The phenotypic f...
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ctla4 alanine 17 confers genetic susceptibility to Graves Disease and to type 1 diabetes mellitus
The Journal of Clinical Endocrinology and Metabolism, 1997Co-Authors: Horst Donner, H. Rau, K. H. Usadel, R. Finke, Paul G. Walfish, J Braun, T Siegmund, J Herwig, Klaus BadenhoopAbstract:The genetic susceptibility to Graves' Disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine Disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' Disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' Disease, 293 patients with IDDM, and 325 controls. Patients with Graves' Disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' Disease as well as to IDDM.
