Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 25, Pages 15119-15124Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2434175100
Keywords
Graves' disease; Hashimoto's disease; thyroiditis
Categories
Funding
- NIDDK NIH HHS [R01 DK061659, DK31755, DK58072, DK61659, R01 DK031775] Funding Source: Medline
- NIMH NIH HHS [R01 MH048858, MH48858] Funding Source: Medline
- NINDS NIH HHS [NS27941, R01 NS027941] Funding Source: Medline
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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.
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