Analysis of thyroglobulin gene polymorphisms in patients with autoimmune thyroiditis

Abstract

The autoimmune thyroid disease is a complex disorder caused by a combination of genetic susceptibility and environmental factors, which are believed to initiate the autoimmune response to thyroid antigens. Identification of the susceptibility genes has found that unique and diverse genetic factors are in association with Graves' disease and autoimmune thyroiditis. The thyroglobulin gene is an identified thyroid-specific gene associated to autoimmune thyroid disease and, principally, with autoimmune thyroiditis. The aim of this work was to test for evidence of allelic association between autoimmune thyroiditis and thyroglobulin polymorphism markers. We studied six polymorphisms distributed throughout all the thyroglobulin gene: four microsatellites (Tgms1, Tgms2, TGrI29 and TGrI30), one insertion/deletion (Indel) polymorphism (IndelTG-IVS18) and one exonic single nucleotide polymorphism (SNP) (c.7589G>A) in 122 patients with autoimmune thyroiditis compared with 100 non-related normal subjects. No differences in allele and genotype distribution were observed between autoimmune thyroiditis cases and controls for Tgms1, Tgms2, TGrI30, IndelTG-IVS18 and c.7589G>A. However, when we analyzed the patients with the TGrI29 microsatellite we found a significant association between the 199-bp allele and AT (33.7% vs. 24.5% in control group) (P = 0.0372). In addition, a higher prevalence of the 201-bp allele has been observed in control subjects (47.5% vs. 38.1% in patients group), although not statistically significant (P = 0.0536). Our work shows the association between the thyroglobulin gene and autoimmune thyroiditis and reinforce that thyroglobulin is a thyroid-specific susceptibility gene for this disease.

Association of the TGrI29 microsatellite in thyroglobulin gene with autoimmune thyroiditis in a Argentinian population: a case–control study

“…We obtained a statistically significant increase in the frequency of the 197-bp allele in the AT population. This finding confirms our previous studies in Spanish populations using the TGrI29 marker, except for that the most frequent allele in these patients is the 199-bp suggesting an allelic heterogeneity [32]. The Argentinian population exhibits an ethnic diversity and includes an important component of Hispanic origin that would explain the similar results in both populations.…”

“…Thyroglobulin (TG) along with thyroid peroxidase (TPO) and TSHR genes encodes the major specific thyroid autoantigens. The TG gene has been identified as the major susceptibility gene for AITD, by linkage and association analysis in Caucasians patients of American [29,30], British [31] and Spanish [32] origin, and in Japanese [33], Taiwanese [34,35] and Chinese [36] population using informative polymorphic markers. In contrast, analysis in Tunisian population [37] and a largest case-control association study in the United Kingdom [38] did not show association of the TG gene with AITD.…”

How Far Are We from Understanding the Genetic Basis of Hashimoto's Thyroiditis?

“…The slightly increased frequency of a microsatellite (namely Tgms2) allele inside the TG gene, in 2.2% of Caucasian AITD patients of British origin (692 GD and 122 HT cases) compared to 0.25% of 790 controls supported the idea of the role of TG in the etiology of AITD [86]. However, because of the rarity of this allele, the authors did not rule out that this finding is just a random chance event; moreover, no such correlation has been found by another group, who tested 122 Caucasian patients with autoimmune thyroiditis and 100 healthy subjects [85]. Association studies of SNPs demonstrated a significant association of the exons 10-12 SNP cluster (resulting in p.A734S, p.P778P, p.V1027M amino acid substitutions) and an exon 33 SNP (p.W1999R) with AITD (285 Caucasian AITD patients, including 193 GD and 92 HT cases) [87], and a strong association of the A/G SNP at position -1623 in the promoter region of TG (rs180195) [26].…”

“…Association studies of SNPs demonstrated a significant association of the exons 10-12 SNP cluster (resulting in p.A734S, p.P778P, p.V1027M amino acid substitutions) and an exon 33 SNP (p.W1999R) with AITD (285 Caucasian AITD patients, including 193 GD and 92 HT cases) [87], and a strong association of the A/G SNP at position -1623 in the promoter region of TG (rs180195) [26]. However, other association studies did not find any correlation between microsatellites [85] or SNP clusters [88] and HT. Similarly, it has also been shown that the c.7589G>A SNP (p.R2511Q) and the IndelTG-IVS18 marker have no impact on autoimmune thyroiditis [85].…”

“…At first, the 8q24 locus containing the TG gene has been reported to be linked with AITD in general [10] or HT alone [16]. Afterwards, different mutations in the gene TG have been identified, spread through its 48 exons, as well as the introns [25,84,85]. The slightly increased frequency of a microsatellite (namely Tgms2) allele inside the TG gene, in 2.2% of Caucasian AITD patients of British origin (692 GD and 122 HT cases) compared to 0.25% of 790 controls supported the idea of the role of TG in the etiology of AITD [86].…”