Association Between Polymorphisms of IL-23/IL-17 Pathway and Clinical Phenotypes of Autoimmune Thyroid Diseases

• Published in: Iranian journal of immunology 2022-06, Vol.19 (2), p.139-149
• Main Authors: Cai, Tiantian, Wang, Guofei, Yang, Yanping, Mu, Kaida, Zhang, Jing, Jiang, Yanfei, Jin-an, Zhang
• Format: Article
• Language: English
• Subjects: Alleles; autoimmune thyroid diseases (aitd); gene-gene interaction; gene-sex interaction; Genetic diversity; Genotype & phenotype; Goiter; Graves disease; Hashimoto's thyroiditis; Helper cells; il-23/il-17 pathway; Inflammatory diseases; Interleukin 17; Interleukin 23; Lymphocytes T; Next-generation sequencing; Phenotypes; Sex; single nucleotide polymorphism (snp); Single-nucleotide polymorphism; Thyroid diseases; Thyroiditis
• ISSN: 1735-1383; 1735-367X
• DOI: 10.22034/iji.2022.93744.2255

Background: Several autoimmune and inflammatory disorders, including autoimmune thyroid diseases (AITD), have been linked to Th17 cells and the IL-23/IL-17 axis. Current data suggest that genetic variation contributes greatly to disease susceptibility to AITD. Objectives: To study the role of single nucleotide polymorphisms (SNPs) of IL-23/IL-17 pathway in AITD predisposition and test the gene-gene/gene-sex interactions in these loci. Methods: A total of 1051 patients with AITD, including 657 patients with Graves' disease (GD) and 394 patients with Hashimoto's thyroiditis (HT), and 874 healthy controls were enrolled in this case-control association study. Six SNPs were selected and genotyped by multiplex PCR combined with high-throughput sequencing. Interactions were tested by the general multifactor dimensionality reduction (GMDR) method. Results: Allele C and combinational genotype AC+CC of rs3212227 within IL-23 were significantly associated with GD with goiter (p=0.003 and 0.014, respectively). Allele G and combinational genotype AG+GG of rs4819554 within IL-17RA were significantly related to HT with family history and the severity of HT (p=0.011 and 0.027; p=0.041 and 0.035). Also, allele T and genotype CT+TT of rs9463772 within IL-17F were significantly correlated with the severity of HT (p=0.001 and 0.027, respectively). Moreover, high dimensional gene-sex interaction (IL-23R-IL-23-IL-17RA-IL-17F-sex) was identified in AITD, GD, and HT patients with GMDR analysis. Conclusions: Our study identified the novel loci and gene-sex interaction in AITD. This evidence, from another perspective, suggests that sex, IL-23/IL-17 pathway, and Th17 cells play an important role in the pathogenesis of AITD.