摘要目的 探讨中国山东临沂地区汉族人群促甲状腺素受体( TSHR)基因内含子1区域单核苷酸多态性(SNP)与Graves病的关系.方法 应用全基因组关联研究(GWAS)和TaqMan探针技术,对1759例GD患者和1740名健康对照者TSHR内含子1区域进行基因分型；同时检测甲状腺激素水平及促甲状腺激素受体抗体(TRAb)水平.结果 选取GWAS研究中发现的5个SNPs位点进入扩大样本的验证,发现rs12101261_T与GD关联性较强(OR=1.257,95％ CI.1.137～1.390,P=8.23× 10-6),logistic回归分析显示rs12101261是GD一个独立致病位点(P=1.61×10-3)；rs12101261_T与治疗1年后TRAb阳性的患者显著相关(OR=1.317,95％CI 1.171～1.481,P=4.14×10-4),与TRAb阴性者无相关性(OR=1.056,95％CI0.892～1.251,P=0.524).rs12101261的3种基因型在TRAb阳性和阴性组的分布差异有统计学意义(P=0.014),其他临床表现差异均无统计学意义(P＞0.05).结论 TSHR基因内含子1区域5个SNP与山东临沂地区汉族人群GD相关,其中rs12101261是一个独立致病位点,该基因多态性与血清TRAb水平相关.

abstractsObjective To investigate the association between single nucleotide polymorphisms in the intron 1 of thyroid stimnulating hormone receptor gene (TSHR) and Graves' disease (GD) in the Chinese Han population from Linyi city,Shandong Province.Methods A total of 1759 GD patients and 1740 control subjects were recruited for genotyping in TSHR intron 1 with genome-wide association study (GWAS) and Taqman probe technique.At the same time,serum thyroid hormone and TSH receptor antibody (TRAb) levels of patients were determined.Results Five SNPs were selected for further replication.The rs12101261 _T was significantly associated with GD risk ( OR=1.257,95％CI 1.137-1.390,P =8.23 × 10-6 ). Logistic regression identified that rs12101261 was an independent susceptibility locus of GD ( P=1.61 × 10-3 ).Furthermore,rs12101261 _T was strongly associated with GD ( OR =1.317,95％ CI 1.171-1.481,P=4.14× 10-4 ) in TRAb positive patients,but no association in TRAb negative patients ( OR=1.056,95％ CI 0.892-1.251,P=0.524 ).Serum TRAb concentration showed remarkable difference among three genotype groups of rs12101261.Conclusions Five SNPs in TSHR intron 1 are associated with GD.rs12101261 contributes to increased GD risk independently and is associated with serum TRAb level.