The haplotype of UBE2L3 gene is associated with Hashimoto’s thyroiditis in a Chinese Han population

Autoimmune thyroid diseases (AITDs) are a set of organ specific endocrine autoimmune diseases mediated by T lymphocyte. They mainly consist of Graves’ disease (GD), Hashimoto’s thyroiditis (HT), and thyroid associated ophthalmopathy (TAO). GD and HT are the most common phenotypes of AITDs. Now the pathogenesis of AITDs is thought to be immune dysfunction due to the interaction between genetic susceptibility and environmental factors. The recent studies have identified more than ten susceptibility loci for AITDs, which include cytotoxic T lymphocyte associated protein 4 (CTLA4) gene [1], thyroid stimulating hormone receptor (TSHR) gene [2], protein tyrosine phosphatase, non receptor type 22 (PTPN22) gene [3], interleukin (IL17) gene [4], thyroglobulin (TG) gene [5], human leukocyte antigen (HLA) gene [6], and FCRL3 gene [7]. The majority of susceptibility genes belong to immunity-related genes.

Ubiquintin proteasome pathway (UPP) is an important signal transduction system which involves many physiological processes. In this pathway, UBE2L3 is an ubiquitin conjugating enzyme (E2) participating in ubiquitination of substrate through sequential steps catalyzed together with activating (E1) and ligase (E3) enzymes, and exerts its degradation effects on targeting molecules [8]. These targeting molecules encompass p53 [9], c-Fos [10] and some immune or inflammatory reaction related molecules such as nuclear factor-κB (NF-κB) [11] and Toll-like receptors (TLR) [12].

Genetic variation in the UBE2L3 has been demonstrated in many autoimmune diseases such as systemic lupus erythematosus (SLE) [13‐15], rheumatoid arthritis (RA) [15, 16] and Crohn’s disease (CD) [17, 18]. As we all know, many different autoimmune diseases often co-exist in one individual or aggregate in different members of one family. More importantly, accumulated evidence indicates that different autoimmune diseases may share common susceptible genes. Therefore, exploring the UBE2L3 gene mutation in the etiology of AITDs is a pivotal issue. In the present case–control study, we analyzed the SNPs in UBE2L3 region, rs131654, rs5754217, rs2298428, rs140489 and rs5998672 in AITDs in a Chinese Han population.

Ubiquitin-mediated specific cellular protein degradation is involved in the regulation of many cellular processes, including cell cycle progression, differentiation, transcriptional adjustment, antigen presenting, receptor signal transduction, tumorigenesis and cell apoptosis [20, 21]. Increasing evidence suggests that UPP is closely related to the occurrence and progression of many autoimmune diseases. UPP’s influence on the immune system is embodied in both innate and adaptive immunities [22]. Under normal circumstances, the body’s innate immune system identifies and combines with intrusive pathogens by such receptors as toll-like receptor (TLR), RIG-1 receptor (RLR), and NOD receptors (NLR), and activates certain transcription factors such as NF-κB, interferon regulatory factor (IRF) family, subsequently inducing the release of various cytokines and inflammatory chemokines to get rid of pathogen from the body. It has been already demonstrated that innate immunity related TLR gene is one of genetic factors for AITDs [23, 24]. The influence of UPP on innate immunity is also controlled negatively by deubiquitylating enzymes (DUBs). As one of the DUBs, TNFAIP3 gene was also showed an association with the AITDs in our previous study [25]. So, studying the relationship between the polymorphisms of UBE2L3 and AITDs is pivotal and interesting. In our study, the frequency of haplotype TCGGC was higher in HT patients than in normal group, This suggests that the genotype which influences the pathogenesis of HT may exist in the vicinity of or in the haplotype itself. That is to say, UBE2L3 gene polymorphism is a predisposing factor for HT occurrence.

Adaptive immunity is generally mediated by T and B lymphocytes. UPP is involved in the regulation of T and B cell functions by adjusting T cell receptor (TCR) and B cell receptor (BCR) signaling transduction. There have been reports on the correlation of five SNPs in UBE2L3 with many T cell or B cell mediated autoimmune diseases, such as SLE [14, 15, 26], RA [15, 16], Crohn’s disease [16, 18], celiac disease [16], Sjögren’s syndrome (SS) and neonatal lupus erythematosus [27]. As a set of complex autoimmune diseases, not only T cell and B cell infiltrate in the lesioned thyroid tissues of AITDs, but also both innate and adaptive immunities may be implicated in its development. It did not come singly but in pairs in the present study, which revealed the relation between UBE2L3 gene variation and the pathogenesis of AITDs.

Although various subtypes of AITDs share common genetic factors and biomarkers, they indeed have their own specific manifestations and probably specific pathophysiolgic mechanisms. We speculated that different clinical types of AITDs may have different prominent alleles and genotypes. But we did not get the predicted result after stratifying the AITDs patients into GD, HT, and TAO ones, cases with positive family history or not, and HT in euthyroid or hypothyroid state.

Herein, our study provide an important clue that SNPs in UBE2L3 are involving in the pathogenesis of HT. Nevertheless, we have to admit this result may be influenced by sample size, different ethnic groups or even different research methods. Further research on UBE2L3 gene in AITDs of other races or even on UBE2L3 gene expression in AITDs is expected in the future.

Thus, we may conclude that UBE2L3 gene variant may be implicated in HT in a Chinese Han population. Further investigations with other ethnic cohorts await to confirm the implication.