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

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.

Molecular Mechanisms in Autoimmune Thyroid Disease

“…These results contrast with other discordant findings, where no associations between IL-2Rα SNPs and the presence of AITD were found [ 147 , 148 , 149 , 150 , 151 ].…”

Genetics, Epigenetics, Cellular Immunology, and Gut Microbiota: Emerging Links With Graves’ Disease

“…It has been reported that CD 25/rs2104286 (case/control: 650/1300; AA genotype: p = 8.772 × 10 −6 , OR = 1.636; A allele: p = 0.004, OR = 1.322) confers to GD susceptibility in the Chinese Han population ( Du et al, 2021 ). The minor allele A (case/control: 1474/1609, p = 0.00017, OR = 1.43) of rs41295061 and the homozygous AA genotype (case/control: 1474/1609, p = 0.0053, OR = 1.54) of rs11594656 conferred susceptibility to GD in a Russian population ( Chistiakov et al, 2011 ).…”

Uncovering the Shared Genetic Components of Thyroid Disorders and Reproductive Health

“…Looking into the genetics, thyroid disorders are considered polygenic and result from the interaction of many genetic variants. A wide range of genes are known to be involved in thyroid dysfunctions, some with hyperthyroidism ( HLA-DR3 , CTLA4 , PTPN22 , CD40 , IL2RA , and FCRL3 ) and others with hypothyroidism ( SLC5A5 , SLC26A4 , TG , TPO , DUOX2 , and DUOXA2 ) (Bufalo et al, 2021; Du et al, 2021; Geysels et al, 2022; Khong et al, 2016; Li et al, 2020; Peters et al, 2019; Pfarr et al, 2006; Ris-Stalpers and Bikker, 2010). However, none of the genes are specific to thyroid disorders (Cortés and Mendieta Zerón, 2019).…”