Common Allelic Variants of Exons 10, 12, and 33 of the Thyroglobulin Gene Are Not Associated with Autoimmune Thyroid Disease in the United Kingdom

Abstract

Thyroglobulin (Tg) is a major autoantigen for autoimmune thyroid disease (AITD). The Tg gene (Tg) has been mapped to chromosome 8q24, which has recently been linked in two independent studies to AITD. Association of specific alleles of microsatellite markers within Tg itself supports a role for Tg as a good candidate susceptibility locus for AITD. Resequencing of the Tg exons has led to the identification of a number of novel single nucleotide polymorphisms, four of which have been reported to be associated with AITD. Resequencing of Tg in Caucasian subjects in the United Kingdom (UK) has confirmed the presence of four single nucleotide polymorphisms in exons 10, 12, and 33. However, in the largest case-control association study to date with adequate power to detect the reported effect if present, we found no evidence for association of the Tg DNA variants with AITD in the UK. These data suggest that the recently identified single nucleotide polymorphisms do not have a causal role for AITD in the UK. At this stage, we cannot exclude the Tg region as harboring a susceptibility locus for AITD, and only large scale sequencing and fine mapping of the region, including neighboring genes, will allow us to identify any potential causal variants within this region.

Association of the TSHR gene with Graves' disease: the first disease specific locus

“…24,25 Briefly, patients were defined as having GD by the presence of biochemical hyperthyroidism together with either the presence of TED or two of the following criteria: diffuse goiter, a significant titre of microsomal (TPO), thyroglobulin (Tg) or TSHR autoantibodies. AIH was diagnosed by the presence of biochemical hypothyroidism together with a significant titre of TPO, Tg or TSHR autoantibodies, with or without a diffuse goiter.…”

Correlation between thyroglobulin gene polymorphisms and autoimmune thyroid disease

“…Tg has an important role in the pathogenesis of AITD (24,25). The Tg gene is a susceptibility gene for AITD (3)(4)(5), and SNPs in the Tg gene were correlated with AITD in animals and humans (3)(4)(5). The present study used the HRMA method to detect Tg SNPs; the HRMA method is simple, accurate, economical, rapid, high-throughput, and can be widely used for the detection of disease-associated gene SNPs and mutations.…”

“…Therefore, disease-associated antigen-specific genes, including those encoding thyroid peroxidase, thyroid-stimulating hormone receptor and thyroglobulin (Tg) comprise another group of candidate genes which are potentially associated with AITD (2). To date, only few studies on Tg and genes associated with the susceptibility to AITD have been performed, and the findings from different population are not consistent (3)(4)(5), possibly due to a range of different detection methods used. Commonly used methods for analyzing differences in gene sequences include single-strand conformation polymorphism (6), denaturing gradient gel electrophoresis (7), denaturing high-performance liquid chromatography (8), temperature gradient capillary electrophoresis (9) and mass spectrometry (10).…”

Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study

“…Weaker replicated effects are also likely to be conferred by the interleukin 2 receptor alpha gene (IL2RA), 14 CD40 15,16 and FCRL 4 with lesser ORs of 1.10-1.30. Other loci in Caucasian subjects have been reported although findings are less consistent (thyroglobulin 17,18 ) or require further replication (including PTPN2 and CD226 19 ). To help identify further susceptibility loci, large-scale genome-wide association studies (comprising 4500 000 SNPs) have been conducted and are at last beginning to deliver novel susceptibility loci for a number of common diseases including the autoimmune diseases.…”