METTL3 gene polymorphisms contribute to susceptibility to autoimmune thyroid disease.

Abstract

Autoimmune thyroid disease (AITD) is a classic autoimmune disorder that mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). In this study, we explored the potential relationship between single-nucleotide polymorphisms (SNPs) of methyltransferase like 3 (METTL3) gene and the development of AITD. The distribution of METTL3 genotypes at seven loci (rs1139130, rs1263790, rs1263791, rs17197156, rs2242526, rs3752411, and rs4417466) in 960 AITD (599 GD and 361 HT) patients and 732 unrelated healthy volunteers was examined using high-throughput sequencing technology in a case-controlled manner and their correlations with AITD development were statistically analyzed. METTL3 genotypes at these seven SNPs were not correlated with both GD and HT except a borderline association between rs3752411and GD after adjusted for age, sex, and thyroid function under the recessive model. Subgroup analysis demonstrated that the minor allele frequencies of rs2242526 and rs4417466 were higher in male AITD patients than in healthy volunteers before adjusted for confounding factors and the genotype distribution of rs4417466 was significantly different between the two groups. Additionally, the genotype frequencies of rs1139130, rs1263791, rs2242526, and rs4417466 were positively related with GD in male patients. Likewise, the allele distribution of rs1263791, rs2242526, and rs4417466 in male GD patients differed significantly from that in male controls. Multivariate logistic regression analyses revealed a significant association between allele frequencies of these three loci and GD in male patients after adjusted for the confounding factors. Moreover, the genotype of rs3752411 was strongly associated with GD in females as well. Furthermore, distribution of rs3752411 genotype was significantly associated with hypothyroidism in HT patients. Our study for the first time revealed a strong correlation between METTL3 mutations and AITD predisposition, implying that METTL3 may be a new candidate gene for AITD treatment.