Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

doi:10.1073/pnas.2434175100

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

^*Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, and ^§Institute for Computational Biomedicine, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, NY 10029; and ^‡Division of Statistical Genetics, Columbia University, New York, NY 10032

Edited by Mark T. Groudine, Fred Hutchinson Cancer Research Center, Seattle, WA (received for review July 6, 2003)

Abstract

The 8q24 locus, which contains the thyroglobulin (Tg) gene, was previously shown to be strongly linked with autoimmune thyroid disease (AITD). We sequenced all 48 exons of the Tg gene and identified 14 single-nucleotide polymorphisms (SNPs). Case control association studies demonstrated that an exon 10-12 SNP cluster and an exon 33 SNP were significantly associated with AITD (P < 0.01). Haplotype analysis demonstrated that the combination of these two SNP groups was more significantly associated with AITD (P < 0.001). Gene-gene interaction studies provided evidence for an interaction between HLA-DR3 and the exon 33 SNP, giving an odds ratio of 6.1 for Graves' disease. We then sequenced exons 10,12, and 33 of the mouse Tg gene in 19 strains of mice. Fifty percent of the strains susceptible to thyroiditis had a unique SNP haplotype at exons 10 and 12, whereas none of the mouse strains that were resistant to thyroiditis had this SNP haplotype (P = 0.01). We concluded that Tg is a susceptibility gene for AITD, both in humans in and in mice. A combination of at least two Tg SNPs conferred susceptibility to human AITD. Moreover, the exon 33 SNP showed evidence for interaction with HLA-DR3 in conferring susceptibility to Graves' disease.

Footnotes

↵ † To whom correspondence should be addressed at: Division of Endocrinology, Diabetes, and Bone Diseases, Box 1055, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029. E-mail: yoshiyuki_ban{at}mssm.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: AITD, autoimmune thyroid disease; Tg, thyroglobulin; SNP, single-nucleotide polymorphism; GD, Graves' disease; HT, Hashimoto's thyroiditis; TSH, thyroid-stimulating hormone; TSHR, TSH receptor; lod, logarithm of odds; EAT, experimental autoimmune thyroiditis; TPO, thyroid peroxidase; INDEL, insertion/deletion; LD, linkage disequilibrium; mTg, mouse Tg; T1D, type 1 diabetes; OR, odds ratio.