Both interleukin-23A polymorphism and serum interlukin-23 expression are associated with Graves’ disease risk

https://doi.org/10.1016/j.cellimm.2015.01.015Get rights and content

Highlights

  • Two independent Chinese cohorts were used to study the genetic association between the IL-23A gene polymorphism (rs11171806) and GD susceptibility.

  • Higher IL-23 concentrations are found in GD patients of older age (⩾40) and female gender.

  • The individuals with A allele of rs11171806 are more vulnerable to Graves’ disease, which suggests that SNP of IL-23 gene may play an important role in GD development.

  • IL-23A gene is a genetic risk marker for GD in China.

Abstract

Two independent Chinese cohorts were used to study the genetic association between the interleukin-23A (IL-23A) gene polymorphism (rs11171806) and susceptibility to Graves’ disease (GD). The initial Shanghai cohort consisted of 712 unrelated patients with GD and 705 healthy control subjects, and the replication cohort from Xiamen Island included 433 patients with GD and 410 healthy control subjects. The serum concentration of IL-23 in GD patients was measured significantly higher than in health controls. Moreover in the subgroup analysis, higher concentrations of IL-23 were identified in patients of older age (⩾40 years) and female gender. We also performed an association study with the IL-23 gene polymorphism rs11171806 in both cohorts, in Shanghai cohorts, the frequencies of rs11171806 alleles were strongly different between Graves’ disease patients (G 95.7% and A 4.3%) and healthy controls (G 97.7% and A 2.3%) (P = 2.6 × 10−3, OR = 1.93 (95% CI: 1.25–2.97)), and in Xiamen cohorts, the proportion of individuals carrying the A allele of rs11171806 was the same significantly higher in Graves’ disease patients than in controls [Graves’ disease vs. control, 4.8% vs. 4.3%, OR = 2.15 (95% CI: 1.23–3.79), Pallele = 6.3 × 10−3]. The distribution of rs11171806 genotype was also investigated in subgroups according to the age and gender. All of these findings suggested that IL-23 may play an important role in the development of GD, and the IL-23A gene is a genetic risk marker for GD in Han Chinese population.

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.

Section snippets

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).

References (34)

  • C. Rong et al.

    Interleukin-23 as a potential therapeutic target for rheumatoid arthritis

    Mol. Cell. Biochem.

    (2012)
  • E. Lee et al.

    Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris

    J. Exp. Med.

    (2004)
  • P.P. Ahern et al.

    The interleukin-23 axis in intestinal inflammation

    Immunol. Rev.

    (2008)
  • Y. Li et al.

    Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia

    Brain

    (2007)
  • C.L. Langrish et al.

    IL-23 drives a pathogenic T cell population that induces autoimmune inflammation

    J. Exp. Med.

    (2005)
  • T. Nanba et al.

    Increases of the Th1/Th2 cell ratio in severe Hashimoto’s disease and in the proportion of Th17 cells in intractable Graves’ disease

    Thyroid

    (2009)
  • S.E. Kim et al.

    Increased serum interleukin-17 in Graves’ ophthalmopathy

    Graefes Arch. Clin. Exp. Ophthalmol.

    (2012)
  • Cited by (19)

    • Graves' disease: Clinical manifestations, immune pathogenesis (cytokines and chemokines) and therapy

      2020, Best Practice and Research: Clinical Endocrinology and Metabolism
      Citation Excerpt :

      These findings indicated that IL-37 exercises a protective role against inflammation in GD, repressing the production of proinflammatory cytokines, and it can be considered a novel target for the pathogenesis and treatment of GD [42]. Two independent Chinese cohorts evaluated the genetic association between rs11171806 (IL-23A gene polymorphism) and susceptibility to GD [43]: the Shanghai cohort (consisting of 712 GD patients and 705 controls), and the replication cohort from Xiamen Island (with 433 GD patients and 410 controls). GD patients had significantly higher circulating IL-23 than control subjects.

    • Chemokines in hyperthyroidism

      2019, Journal of Clinical and Translational Endocrinology
      Citation Excerpt :

      In Shanghai cohorts, the frequencies of rs11171806 alleles were markedly different between GD patients (G 95.7% and A 4.3%) and healthy controls (G 97.7% and A 2.3%) [P = 2.6 × 10−3, OR = 1.93 (95% CI: 1.25–2.97)], and in Xiamen cohorts, the proportion of individuals carrying the A allele of rs11171806 was high both in GD patients and in controls, in a similar manner [GD vs. control, 4.8% vs. 4.3%, OR = 2.15 (95% CI: 1.23–3.79), Pallele = 6.3 × 10−3]. These data indicated that in GD the IL-23A gene could be a genetic risk marker in Han Chinese population [72]. The association between IL-6 -174 G/C polymorphism and GD have been investigated by various studies, with discordant results.

    • Young and Aged Blunt Trauma Patients Display Major Differences in Circulating Inflammatory Mediator Profiles after Severe Injury

      2019, Journal of the American College of Surgeons
      Citation 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

    • Graves’ disease: Introduction, epidemiology, endogenous and environmental pathogenic factors

      2018, Annales d'Endocrinologie
      Citation 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.

    View all citing articles on Scopus
    1

    Huiying Jia, Feng Tao and Changqin Liu contributed equally to this work.

    View full text