Association of established thyroid peroxidase autoantibody (TPOAb) genetic variants with Hashimoto’s thyroiditis

Abstract

Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid diseases (AITD) characterized by progressive destruction of thyroid tissue that may lead to hypothyroidism. High thyroid autoantibodies against thyroid peroxidase (TPOAb) levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. The main aim of our study was to test whether recently identified genetic variants associated with TPOAb are also involved in HT development. A total of 504 unrelated individuals, including 200 patients with HT and 304 controls, were involved in this study. Diagnosis of HT cases was based on clinical examination, measurement of thyroid hormones (TSH and fT4) and antibodies (TgAb, TPOAb) and ultrasound examination. We selected and genotyped 14 known TPOAb-associated genetic variants. Case-control logistic regression model was used to test the association of selected genetic variants with HT. Additionally, we tested association of the same genetic variants with thyroid related quantitative traits (TPOAb levels, TgAb levels and thyroid gland volume) using linear regression. Three genetic variants showed nominal association with HT; rs10774625 in ATXN2 gene (p = 0.0149, OR = 0.73, CI = 0.56-0.94), rs7171171 near RASGRP1 gene (p = 0.0356, OR = 1.4, CI = 1.02-1.92) and rs11675434 in TPO gene (p = 0.041, OR = 1.31, CI = 1.01-1.69). Two of these SNPs (rs1077462, rs11675434) also showed association with TPOAb levels (p = 0.043, β = -0.39; p = 0.042, β = 0.40, respectively) and one (rs7171171) was associated with thyroid gland volume (p = 0.0226, β = -0.21). Our findings suggest that variants inside or near TPO, ATXN2 and RASGRP1 genes are associated with HT. Identified loci are novel to HT and represent good basis for further exploration of HT susceptibility.

WITHDRAWN: Target region sequencing and gene polymorphism of Chinese Uyghur individuals with autoimmune thyroid diseases (AITDs)

“…These results seemed to reflect that certain loci of above genes could be associated with AITDs Uyghur patients in [20,21]. In recent decades, a number of SNPs in the TPO gene have been genotyped and different loci showed different effect on ATIDs (both GD and HT, or respectively), which further clarified the important role of TPO played in the development of AITDs [21][22][23][24]. TG is a 660-kDa glycoprotein, which accounts for about 75%-80% of the total thyroid protein [25,26] and deserves to be a major AITDs susceptibility gene.…”

“…In our first genome screen, performed with 100 AITDs Uyghur patients (50 GD and 50 HT) and 50 Uyghur controls, seven SNPs of four genes showed evidence for linkage with AITDs Uyghur patients (Tables 2 and 3): four SNPs (rs62117031, rs62117032, rs4278970 and rs4927631) of TPO gene and one SNP (rs2702998) of TG gene elevated in AITDs patients; otherwise rs2284735 of TSHR gene and rs16843742 of PTPRC gene received an opposite consequence. These results seemed to reflect that certain loci of above genes could be associated with AITDs Uyghur patients in [20,21]. In recent decades, a number of SNPs in the TPO gene have been genotyped and different loci showed different effect on ATIDs (both GD and HT, or respectively), which further clarified the important role of TPO played in the development of AITDs [21][22][23][24].…”

Association between TPO Asn698Thr and Thr725Pro gene polymorphisms and serum anti-TPO levels in Iranian patients with subclinical hypothyroidism

“…They suggested that genetic variations in or near the TPO gene are associated with HT. 2 Balmiki et al have demonstrated that two TPO gene polymorphisms, namely Thr725Pro (rs732609) and Asp666Asp (rs1126797), had a significant correlation with those of Indian patients with hypothyroidism. 15 Similarly, we were also able to show the significant relationship between the Thr725Pro (A2173C) gene polymorphism of TPO and patients who had elevated serum TSH, but not FT3 and FT4, who were identified as having subclinical hypothyroidism.…”

“…1,2 Subclinical hypothyroidism (SCH) is defined as high serum thyrotropin or thyroid stimulating hormone (TSH) and normal levels of free thyroxine (FT4). 3 Subclinical hypothyroidism is mild thyroid failure: it is a common condition with a prevalence of 3% to 8% in the population without known thyroid disease.…”

Thyroid Peroxidase Revisited – Whatʼs New?

“…Interestingly, a recently identified type of natural bispecific antibody against TPO and Tg may play a protective role in the pathogenesis of HT [20]. Extensive studies conducted by various groups on genetic loci associated with the presence of TPOAbs revealed their localization, for example, in the HLA region and inside or near genes encoding TPO, TSH receptor (TSHR), and Tg [21][22][23][24][25][26][27].…”