A case–control study of selenoprotein genes polymorphisms and autoimmune thyroid diseases in a Chinese population

Selenium is an essential trace element and its distribution in nature varies widely. The soil of central and southern European countries is generally poor in selenium content, resulting in mild regional selenopenia, whereas in most North American regions it is abundant. Severe selenopenia was observed in large areas of central Asia. Selenium is present in the active site of selenoproteins, which are crucial to immune function, inflammation, redox processes and important for thyroid hormone synthesis and metabolism. There is a high selenium concentration in the thyroid gland, and selenium deficiency may impair the thyroid function. Reactive oxygen species (ROS), formed from thyroid hormone metabolism, may cause damage to different cellular structures and trigger tissue inflammation. Selenoproteins, which are powerful antioxidant enzymes, mitigate the effects of oxidative stress by elimination of ROS. In addition, selenoproteins play a vital role in the regulation of human immune system and Se deficiency is accompanied by dysregulation of both cell-mediated immunity and B cell function.

Autoimmune thyroid diseases (AITD), mainly including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are the most frequent autoimmune disorders. GD is characterized clinically by hyperthyroidism, diffuse goiter and the presence of thyrotropin receptor antibodies (TRAb), while HT is characterized by apoptosis of thyrocytes leading to hypothyroidism and the presence of thyroid peroxidase antibodies (TPOAb) or antibodies against thyroglobulin (TGAb). Autoimmune thyroid disease (AITD) is a multifactorial disease in which autoimmunity against thyroid antigens develops against a particular genetic background facilitated by exposure to environmental factors. Environmental factors include smoking, vitamin D, iodine, selenium and so on. GD and HT also share some but not all susceptible genes.

The value of selenium supplementation in autoimmune thyroid disorders had been investigated and most studies confirmed the beneficial effect of selenium supplementation in Hashimoto’s and Graves’s diseases, though some studies showed conflicting results as well [1–11]. Recently, selenium was proved to be effective in mild inflammatory thyroid associated orbitopathy (TAO) too [12]. Different selenium nutrition state in different studies may partly explain different reactivity to the selenium supplementation, different genetics factors in different populations may be another reason. Few studies were done about the association of selenoprotein genetic variations in AITD.

The role for selenium supplementation in the treatment of autoimmune thyroid diseases is still unresolved. Clinic studies provide evidence for a preventive effect of selenium on autoimmune thyroid disease, which may be mediated by the antioxidative and anti-inflammatory properties of selenoproteins, we therefore investigated whether genetic variants in selenoproteins are associated with GD and HT. Among 25 selenoproteins known to date, various functions are characterized for each of them. These include Se transport (selenoprotein P), antioxidant/redox properties (glutathione peroxidases (GPxs), thioredoxin reductases and selenoprotein P) and anti-inflammatory properties (selenoprotein S and GPx4). We chosed to study SNPs rs6865453 in selenoprotein P gene (SELENOP), rs713041 rs2074451 rs3746165 in glutathione peroxidase 4 gene (GPX4), rs28665122 and rs7178239 in selenoprotein S gene (SELENOS) in a Han Chinese population.

Selenium is incorporated into selenoproteins implicated in antioxidative defence, thyroid hormone metabolism and immunoregulation. Selenoproteins are important for the thyroid function and the thyroid health. Selenium metabolism is controlled by hepatocytes synthesizing and secreting the Se transporter selenoprotein P (SePP). SePP, encoded by SELENOP gene, is a liver-derived plasma protein and the major selenium containing protein in serum. Serum levels of SePP in humans are considered a biomarker of selenium status in the entire body. Its promoter activity has been shown to be inhibited by cytokines including interleukin 1β, tumor necrosis factor α, interferon γ and transforming growth factor β1 [15, 16], suggesting a role of SELENOP in the process of inflammation. SePP is able to bind to the endothelium and be recruited to the site of the inflammation. It also has the ability to bind epithelial cells and displays phospholipid hydroperoxide thiol peroxidase activity [17]. Overexpression of SELENOP suppressed hydrogenperoxide-induced activation of JNK and p38 whereas the gene’s knocked-down led to increased production of lipid hydroperoxide [18]. Studies showed that genetic variants in SELENOP were associated with the risk of breast cancer, prostate cancer, advanced colorectal adenoma and colorectal cancer as well as first phase insulin response and the occurrence of abdominal aortic aneurysm [19–24]. No studies about their roles in AITD were reported. We detected the association of rs6865453 in SELENOP with AITD, but it was negative.

Phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) is an intracellular selenoprotein, a major antioxidant enzyme, which plays unique roles in the protection of cells against oxidative stress by catalysing reduction of lipid hydroperoxides. GPX4 may also play a role in regulation of leukotriene biosynthesis and cytokine signaling pathways [25, 26]. GPx4 rs713041 polymorphisms could modulate the synthesis and expression of GPx4 by altering the selenocysteine insertion [27, 28]. GPx4 rs713041 were found to be associated with breast cancer mortality, the risk of colorectal cancer and cerebral stroke [23, 29, 30]. GPx4 rs2074451 variant was also found to be associated with breast cancer survival [24]. And rs3746165 variants in GPx4 may be associated with risk of lethal prostate cancer [31]. No relevance of these SNPs to AITD was reported. We detected these three GPx4 SNPs in this case–control study, but no association with AITD was found.

Selenoprotein S (SELENOS, gene aliases: SELS, VIMP, TANIS) has been classified as a new endoplasmic reticulum (ER) membrane protein that moves misfolded proteins from the ER to the cytosol and prevents stress responses that activate the inflammatory cascade [32]. It is a membrane-bound selenoprotein and located in ER and other plasma membrane. It protects cells from oxidative damage and it impacts the immune and inflammatory signal pathways. It is expected that genetic polymorphisms affecting SELENOS gene transcription and subsequent SELENOS expression levels might contribute to the development and progression of inflammatory disorders. A previous study discovered that a functional single nucleotide polymorphism (SNP) in the SELENOS promoter region (G-105A, rs28665122) impairs SELENOS expression and amplifies the production of inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and interleukin-1b (IL-1b) [33]. No significant differences were observed in the genotypic distribution of the SELENOS polymorphisms analyzed in Spanish cohorts between patients suffering from autoimmune diseases with a clear inflammatory component, like T1D, RA or IBD and controls [34]. While the SELENOS rs28665122 polymorphism had been found to be associated with the risk of spontaneous preterm birth in a Chinese population [35], the existence of association between this genetic variation and HT risk was also found in a Portuguese population with a higher allele A proportion in the patient group [14]. Here we detected the link between rs28665122 and rs7178239 polymorphisms in SELENOS gene and AITD in a Chinese population. Unfortunately, the association between AITD risk and these two SELENOS SNPs in our study was negative. Opposing to the result from the Portuguese population, the allele C and CC genotype in SELENOS rs28665122 increased in HT patients in our study. Inconsistent result suggests that different genetic variants may be involved in the etiology of AITD in different populations. Different pathogenic mechanisms may underlie autoimmune thyroid disease in different populations. This may partly explain the conflicting effects of selenium administration on AITD antibodies in studies from different populations. Different selenium nutrition status of the population from different geographical location may be another factor contributing to this inconsistent result. Clearly, further in-depth studies and evaluation are required concerning the mechanism of selenium action and the etiology of AITD.

Our findings suggested non-association between six SNPs of three selenprotein genes and AITD, non-association between SNPs and clinical genotypes. Our results were conflicted to the result from the Portuguese population study. In that study, the higher allele A in SELENOS rs28665122 had been found to be associated with the HT risk [14]. Different selenium nutrition state in different populations may contribute to conflicting results, the contribution of genetic variants in AITD mechanism may be another reason.