Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China.
Iran J Immunol. 2022 Jun;19(2):139-149. doi: 10.22034/iji.2022.93744.2255.
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.
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.
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.
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.
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.
包括自身免疫性甲状腺疾病（AITD）在内的几种自身免疫和炎症性疾病与 Th17 细胞和 IL-23/IL-17 轴有关。目前的数据表明，遗传变异对 AITD 的易感性有很大影响。
研究 IL-23/IL-17 通路中单核苷酸多态性（SNP）在 AITD 易感性中的作用，并检测这些基因座中的基因-基因/基因-性别相互作用。
这项病例对照关联研究共纳入了 1051 名 AITD 患者，包括 657 名格雷夫斯病（GD）患者和 394 名桥本甲状腺炎（HT）患者，以及 874 名健康对照者。通过多重 PCR 结合高通量测序选择并检测了 6 个 SNP。采用一般多因子降维（GMDR）方法检测相互作用。
IL-23 内 rs3212227 的等位基因 C 和组合基因型 AC+CC 与 GD 伴甲状腺肿显著相关（p=0.003 和 0.014）。IL-17RA 内 rs4819554 的等位基因 G 和组合基因型 AG+GG 与 HT 伴家族史和 HT 严重程度显著相关（p=0.011 和 0.027；p=0.041 和 0.035）。此外，IL-17F 内 rs9463772 的等位基因 T 和基因型 CT+TT 与 HT 的严重程度显著相关（p=0.001 和 0.027）。此外，通过 GMDR 分析，在 AITD、GD 和 HT 患者中发现了高维基因-性别相互作用（IL-23R-IL-23-IL-17RA-IL-17F-性别）。
本研究在 AITD 中确定了新的基因座和基因-性别相互作用。从另一个角度来看，这些证据表明，性别、IL-23/IL-17 通路和 Th17 细胞在 AITD 的发病机制中发挥着重要作用。
