Both interleukin-23A polymorphism and serum interlukin-23 expression are associated with Graves’ disease risk
Introduction
Graves’ disease (GD) is one of the most common and complex autoimmune disorders. The patients with GD frequently have overactive thyroid that produces an increased level of thyroid hormone with a wide range of immunologic features [1], [2]. Previous studies have indicated that cytokines play important roles in tissue inflammation, and aberrant expression of cytokine is believed to participate in the pathogenesis of GD [3]. Interleukin-23 (IL-23), a pro-inflammatory cytokine that belongs to the IL-12 cytokine family, is a potential contributor to the regulation of cellular immune responses [4], [5]. Over the past few years, multiple lines of evidence have suggested that IL-23 is involved in the etiology of various human immune disorders including psoriasis, inflammatory bowel diseases, rheumatoid arthritis, and multiple sclerotic lesions [4], [6], [7], [8], [9]. Moreover, by effecting on the differentiation of T helper 17 (Th17) cells, IL-23 has been recognized as a potent cytokine to the development of certain Th17-mediated autoimmune diseases such as GD [4], [10], [11]. In patients with GD, both increased frequency of Th17 cells and enhanced production of IL-17 were observed [12], [13], [14]. However, there has been no study that directly showed the association of IL-23 to the risk of GD. The role of IL-23 in the pathogenesis of GD is still poorly understood and the precise mechanism of its involvement is not elucidated.
On the other hand, GD is a multifactorial autoimmune disorder, and evidences from genetic analyses have suggested a strong genetic component to GD [15], [16], [17]. Genetic association studies, including the early linkage analysis and most recently genome-wide association screening, have identified several GD susceptibility candidate genes such as major histocompatibility complex, thyroid-stimulating hormone receptor (TSHR), toll-like receptor, and programmed death ligand 1 [18], [19], [20]. IL-23 is a heterodimeric cytokine consisting of two subunits: a p40 subunit encoded by the IL-23A gene and a p19 subunit encoded by the IL-12B gene [4]. Recently, several IL-23-related genes such as the IL-23 receptor gene and the IL-17A gene have been shown to be associated with susceptibility to GD [21], [22]. These results imply that the IL-23 gene may be a candidate gene predisposing to GD. Previous genetic linkage studies have been performed on polymorphisms of the IL-12B gene in patients with GD in the Asian populations; however, no statistical association was found [23], [24]. To investigate the genetic contribution of IL-23 in the pathogenesis of GD, the first genetic association analysis between polymorphism of the IL-23A gene and GD in two independent Han Chinese populations was performed, which revealed a significant correlation between the IL-23A gene variant and GD. Furthermore, the IL-23 serum level in patients with GD was also evaluated, which found a strong association between the IL-23 serum level and patients with GD.
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Study population
Two independent Han Chinese cohorts of patients with GD and control subjects were enrolled in the present study. In the initial cohort, 712 unrelated patients with GD (186 men and 526 women; age range, 10–81 years; mean, 38.7 ± 13.4 years) and 705 healthy control subjects (163 men and 542 women; age range, 20–85 years; mean, 42.3 ± 15.5 years) were enrolled at Ruijin Hospital in Shanghai (eastern China). All patients with GD were diagnosed based on the clinical manifestations and biochemical
Association study of the rs11171806 polymorphism in the two cohorts
IL-23A gene contains four exons and three introns, and there are seven SNPs located within the gene region (including the untranslated regions, Fig. S1). Within them, only the locus of rs11171806 is polymorphic in the Han Chinese population according to the HapMap project (Table S1), and thus this polymorphism was focused. The genotype and allele distributions of rs11171806 are shown in Tables 1 and 2. The genotypic frequencies in patients with GD and healthy control subjects of the two cohorts
Discussion
Over the past two decades, with the identification of the Th17 cell subset, studies on the pathogenesis of GD were gradually shifted from the Th1/Th2 paradigm to the IL-23/Th17 axis [21], [29], [30], [31]. In this study, the serum level of IL-23 was measured as well as a genetic association study of the IL-23A gene and the risk of GD, which demonstrated an important role of IL-23 in the pathogenesis of GD.
IL-23 is a potent cytokine in the regulation of various human autoimmune diseases.
Acknowledgments
The present study would not have been possible without the participation of the patients and healthy volunteers. The study was partly supported by the Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Public Health (No. 1994DP131044), National Natural Science Foundation of China (No. 81170712) and the Shanghai Municipal Natural Science Foundation (No. 11495803400).
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2019, Journal of the American College of SurgeonsCitation Excerpt :It is a pro-inflammatory cytokine that plays a role in the differentiation of T helper 17 cells in type 3 immunity.23 It has been identified as a key mediator in inflammatory and autoimmune diseases, including inflammatory bowel disease, inflammatory joint disease, and Graves disease.25-27 In mouse studies of hemorrhagic shock, IL-23 has been shown to be a driver of lung polymorphonuclear leukocyte infiltration and IL-17A.28
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2018, Annales d'EndocrinologieCitation Excerpt :A very large number of other genes have been identified on genome-wide linkage or association studies as predisposing to or on the contrary protective against Graves’ disease [45,68]. More recently, even more genes were identified, including the genes coding for cytokines, TLR or TPO [69–73]. These studies need replicating before all of these genes can be confirmed and the mechanisms of the predisposing or protective effects be analyzed.
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Huiying Jia, Feng Tao and Changqin Liu contributed equally to this work.