Limited genetic susceptibility to severe graves' ophthalmopathy: No role for CTLA-4 but evidence for an environmental etiology

R. Villanueva, A. M. Inzerillo, Yaron 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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Abstract

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. Seventyseven 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-β (TNF-β), 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.

Original languageEnglish (US)
Pages (from-to)791-798
Number of pages8
JournalThyroid
Volume10
Issue number9
StatePublished - 2000
Externally publishedYes

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Graves Ophthalmopathy
Genetic Predisposition to Disease
Graves Disease
Thyroid Diseases
Autoimmune Diseases
HLA Antigens
Genes
Thyrotropin Receptors
Hashimoto Disease
Heredity
Hyperthyroidism
Nuclear Family
Age of Onset
Tumor Necrosis Factor-alpha
Smoking

ASJC Scopus subject areas

  • Endocrinology

Cite this

Villanueva, R., Inzerillo, A. M., Tomer, Y., Barbesino, G., Meltzer, M., Concepcion, E. S., ... Davies, T. F. (2000). Limited genetic susceptibility to severe graves' ophthalmopathy: No role for CTLA-4 but evidence for an environmental etiology. Thyroid, 10(9), 791-798.

Limited genetic susceptibility to severe graves' ophthalmopathy : No role for CTLA-4 but evidence for an environmental etiology. / Villanueva, R.; Inzerillo, A. M.; Tomer, Yaron; Barbesino, G.; Meltzer, M.; Concepcion, E. S.; Greenberg, D. A.; MacLaren, N.; Sun, Z. S.; Zhang, D. M.; Tucci, S.; Davies, T. F.

In: Thyroid, Vol. 10, No. 9, 2000, p. 791-798.

Research output: Contribution to journalArticle

Villanueva, R, Inzerillo, AM, Tomer, Y, Barbesino, G, Meltzer, M, Concepcion, ES, Greenberg, DA, MacLaren, N, Sun, ZS, Zhang, DM, Tucci, S & Davies, TF 2000, 'Limited genetic susceptibility to severe graves' ophthalmopathy: No role for CTLA-4 but evidence for an environmental etiology', Thyroid, vol. 10, no. 9, pp. 791-798.
Villanueva R, Inzerillo AM, Tomer Y, Barbesino G, Meltzer M, Concepcion ES et al. Limited genetic susceptibility to severe graves' ophthalmopathy: No role for CTLA-4 but evidence for an environmental etiology. Thyroid. 2000;10(9):791-798.
Villanueva, R. ; Inzerillo, A. M. ; Tomer, Yaron ; Barbesino, G. ; Meltzer, M. ; Concepcion, E. S. ; Greenberg, D. A. ; MacLaren, N. ; Sun, Z. S. ; Zhang, D. M. ; Tucci, S. ; Davies, T. F. / Limited genetic susceptibility to severe graves' ophthalmopathy : No role for CTLA-4 but evidence for an environmental etiology. In: Thyroid. 2000 ; Vol. 10, No. 9. pp. 791-798.
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abstract = "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. Seventyseven 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-β (TNF-β), 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.",
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AU - Concepcion, E. S.

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