PDF(Pubmed)
Abstract：
Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5\'-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10-16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10-3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.
摘要：
自身免疫性甲状腺疾病(AITD)是一种常见的自身免疫性疾病。在110,945例和1,084,290例对照的GWAS荟萃分析中，225个基因座处的290个序列变体与AITD相关。在这些变体中，115以前未报告。多组学分析产生了MHC区外的235个候选基因，该发现强调了参与T细胞调节的基因的重要性。一种罕见的5'-UTR变体(rs781745126-T，MAF=冰岛的0.13％）在LAG3中具有最大的作用（OR=3.42，P=2.2×10-16），并为规范蛋白翻译起始位点上游的开放阅读框产生新的起始密码子。rs781745126-T减少了活化淋巴细胞亚群上抑制性免疫检查点LAG-3共受体的mRNA和表面表达，并在杂合子中降低了血浆中LAG-3水平。rs781745126-T的所有三个纯合携带者都具有AITD，其中一人还患有另外两种T细胞介导的疾病，那就是白癜风和1型糖尿病。rs781745126-T名义上与白癜风相关（OR=5.1，P=6.5×10-3），但与1型糖尿病无关。因此，rs781745126-T的作用类似于抑制LAG-3的药物,LAG-3可释放免疫反应,并可导致甲状腺功能障碍和白癜风作为不良事件.这说明了多组学方法如何揭示潜在的药物靶标和安全性问题。
