Document Detail


Limited genetic susceptibility to severe Graves' ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology.
MedLine Citation:
PMID:  11041456     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Graves' disease (GD) is an autoimmune thyroid disease (AITD) characterized by hyperthyroidism and by the occurrence of a distinctive ophthalmopathy (orbitopathy), which presents with varying degrees of severity. Graves' disease clusters in families but the importance of heredity in the pathogenesis of the associated ophthalmopathy is unclear. We have studied the family history of 114 consecutive, ethnically mixed patients with severe Graves' ophthalmopathy (GO). Patients were selected by unambiguous single ascertainment. Seventy-seven percent of patients were female and 59% smoked. The mean age at onset of their GD was 43 years (range 17-78 years). Forty-one patients (36%) had a family history of AITD, defined as a first- and/or a second-degree relative affected with either Graves' disease (GD) or Hashimoto's thyroiditis (HT). The segregation ratio for AITD in nuclear families in our ascertained Graves' ophthalmopathy families was 0.07 (0.12 in Caucasians only). Hence, the higher prevalence of AITD among relatives of Graves' ophthalmopathy patients agreed with the known genetic predisposition to AITD and this predisposition was stronger in women than in men. However, only 3 of the 114 patients had a family history of severe Graves' ophthalmopathy (all second-degree relatives) and the segregation ratio for GO was 0. These data did not support a major role for familial factors in the development of severe Graves' ophthalmopathy distinct from Graves' disease itself. In addition, we tested 4 candidate genes, human leukocyte antigen (HLA), tumor necrosis factor-beta (TNF-beta), CTLA-4 and the thyrotropin receptor (TSHR), for association with Graves' ophthalmopathy. These were negative except for the HLA and CTLA-4 genes, which were found to be weakly associated with GO giving similar relative risk (RR) as in GD patients without ophthalmopathy. These data suggested that environmental factors, rather than major genes, were likely to predispose certain individuals with AITD to severe Graves' ophthalmopathy. Smoking remains one example of such potential external insults.
Authors:
R Villanueva; A M Inzerillo; Y Tomer; G Barbesino; M Meltzer; E S Concepcion; D A Greenberg; N MacLaren; Z S Sun; D M Zhang; S Tucci; T F Davies
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Thyroid : official journal of the American Thyroid Association     Volume:  10     ISSN:  1050-7256     ISO Abbreviation:  Thyroid     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2001-01-17     Completed Date:  2001-02-01     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  9104317     Medline TA:  Thyroid     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  791-8     Citation Subset:  IM    
Affiliation:
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aged
Antigens, CD
Antigens, Differentiation / genetics*
CTLA-4 Antigen
Continental Population Groups
Environment*
Female
Genetic Predisposition to Disease*
Graves Disease / etiology*,  genetics*
Histocompatibility Testing
Humans
Immunoconjugates*
Lymphotoxin-alpha / genetics
Male
Middle Aged
Receptors, Thyrotropin / genetics
Grant Support
ID/Acronym/Agency:
DK35764/DK/NIDDK NIH HHS; DK45011/DK/NIDDK NIH HHS; DK52464/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, Differentiation; 0/CTLA-4 Antigen; 0/CTLA4 protein, human; 0/Immunoconjugates; 0/Lymphotoxin-alpha; 0/Receptors, Thyrotropin; 7D0YB67S97/abatacept

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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