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Predisposition to Graves’ disease and Graves’ ophthalmopathy by genetic variants of IL2RA

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Abstract

Previous studies have identified that Th17/Treg cells were involved in the occurrence and development of Graves’ disease (GD). This study aimed at clarifying the association between GD susceptibility and nine single nucleotide polymorphisms (SNPs) of Th17/Treg cell-related genes, including IL2RA, miR27a, miR182, and FoxO1. A two-stage association study was performed in 650 GD patients and 1300 healthy controls. PCR–RFLP assays, real-time PCR, and ELISA were performed. In the first stage, association analysis has identified that IL2RA/rs3118470 TT genotype (Pc = 0.027, OR = 1.688) and IL2RA/rs2104286 AA genotype (Pc = 0.027, OR = 1.658) has significantly increased frequencies in patients with GD than control subjects. In the second stage, the result of rs2104286 was consistent with the first-stage results (AA genotype: Pc = 0.006, OR = 1.618). The combined data showed that IL2RA/rs2104286 AA genotype had increased frequencies in patients with GD (Pc = 8.772 × 10−6, OR = 1.636). Stratification analysis also revealed that rs2104286 AA genotype was significantly associated with Graves’ ophthalmopathy (GO) susceptibility (Pc = 9.150 × 10−4, OR = 1.851). Functional studies showed that carriers of the rs2104286 AA genotype had lower IL2RA mRNA expression than AG genotype carriers (P = 0.021). Cytokine analyses revealed that the rs2104286 AA genotype individuals had lower IL-10 levels (P = 0.015) and increased IL-17 levels than AG genotype carriers (P = 1.467 × 10−4). In conclusion, our findings suggested that IL2RA/rs2104286 was associated with GD and GO susceptibility in Southwest Chinese Han population, which may be involved in the occurrence of GD and GO by affecting the mRNA expression of IL2RA gene and the cytokine production.

Key messages

  • We identified that IL2RA/rs2104286 locus contributed to the predisposition of Graves’ disease (GD) and Graves’ ophthalmopathy (GO).

  • Functional analyses suggested that IL2RA/rs2104286 may participate in the occurrence of GD and GO by affecting the mRNA expression of IL2RA and cytokine (IL-10 and IL-17) secretion.

  • We found that IL2RA (rs3118470, rs7093069), miR27a/rs895819, miR182/rs76481776, and FoxO1 (rs2297626, rs17592236, rs9549241, rs12585277) loci polymorphisms were not associated with GD susceptibility.

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Funding

This work was supported by National Key R&D Program of China (grant number 2018YFC1004300), National Natural Science Foundation Project of China (grant number 81670844), the Key Project of Guizhou Provincial Science and Technology Department (grant number QKH-JC-2019–1464), the Excellent Talent Support Program of Guizhou Provincial Education Department (grant number QJH-KY-2017–077), the Science and Technology Foundation of Guizhou Province (grant number QKH-PTRC-2017–5733-003, QKH-PTRC-2018-5772-042), and the Program for Excellent Young Talents of Zunyi Medical University (grant number 18-ZY-001), the science and technology program project of Zunyi (ZSKH-HZ-2020–35) and the project of Scientific Research Foundation for Postgraduates of Guizhou Province (grant number QJH-YJSCXJH-2019–094).

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Authors and Affiliations

  1. School of Basic Medical Science, Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi, 563000, China

    Juan Du, Xin Wang, Guiqin Tan, Wenwen Wei, Fangyu Zhou, Zhongzhi Liang & Hongsong Yu

  2. Yongchuan Hospital, Chongqing Medical University, Chongqing, 402160, China

    Hua Li

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  1. Juan Du
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  2. Xin Wang
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Correspondence to Hongsong Yu.

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Du, J., Wang, X., Tan, G. et al. Predisposition to Graves’ disease and Graves’ ophthalmopathy by genetic variants of IL2RA. J Mol Med 99, 1487–1495 (2021). https://doi.org/10.1007/s00109-021-02111-0

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