成人隐匿性自身免疫糖尿病多基因分子遗传学关联研究

Latent autoimmune diabetes in adults (LADA) occurring has a relatively slow and latent onset, which represents patients with type 2 diabetic (T2DM) phenotypes. However, it is essentially a subgroup of type 1 diabetes (T1DM). And it is usually misdiagnosed and mistreated as T2DM patients in clinical practice. LADA patients are distributed widely in China because of large population base. The precondition for effective prevention and treatment of LADA is early screening and correct diagnosis. In this instance, it plays undoubtedly a critical role for diseases screening and diagnosis to determine LADA's major susceptibility gene. However, the genetics analysis of LADA in Chinese is lack of relevant data. And it is poorly understood compared those in other countries. At the early stage, we have investigated molecular genetics association of HLA-DR-DQ genes with T1DM . This project aims to further study the effect of major genes including HLA-DRB1, DQA1 and DQB1 in T1DM on LADA in Chinese Han. At the same time, the effect of IFIH1 gene, a newly discovered gene susceptibility to T1DM, and TCF7L2 gene, a major predisposing gene to T2DM, on LADA will be also explored. Furthermore, we will analyze the variation of these predisposing genes in different subtypes of diabetes and association between these genes and islet autoantibodies,βcell function. These data may reveal the genetics essence of LADA to a certian extent. It will lay a strong foundation for early genetic screening, disease forecasting and immunologic intervention of LADA.

成人隐匿性自身免疫糖尿病(LADA)缓慢隐匿起病，临床表现貌似2型糖尿病(T2DM)，但本质上属1型糖尿病(T1DM)，极易被误诊误治。我国人口基数大，LADA受累人群广，有效防治LADA的前提是进行早期筛查及正确诊断，而LADA遗传易感基因的探讨对疾病筛查与诊断无疑起着十分重要的作用。我国LADA遗传学研究数据缺乏，同国外研究相比相距甚远。前期我们已对T1DM与HLA- DR-DQ基因进行了分子遗传学研究，本项目拟进一步研究T1DM的主效基因HLA-DRB1、DQA1和DQB1基因与中国LADA的分子遗传学关系，同时探讨新发现的T1DM易感基因IFIH1以及T2DM最主要的易感基因TCF7L2在LADA中的遗传作用，及分析这些易感基因在不同糖尿病亚型中的变化规律，与胰岛自身抗体、β细胞功能的关系，有望揭示中国LADA遗传学本质，为LADA早期遗传筛查、发病预测和免疫干预奠定坚实的基础。

成人隐匿性自身免疫糖尿病(LADA)缓慢隐匿起病，临床表现貌似2型糖尿病(T2DM)，但本质上属1型糖尿病(T1DM)，极易被误诊误治。LADA遗传易感基因的探讨对疾病筛查与诊断起着十分重要的作用。本项目主要研究了T1DM的主效基因HLA-DRB1、DQA1和DQB1基因与中国LADA的分子遗传学关系，同时探讨了非HLA基因在LADA中的遗传作用。本项目发现DRB1*0405-DQA1*03-DQB1*0401 (DR4, 7.6%)与DRB1*0901-DQA1*03-DQB1* 0303 (DR9, 22.3%)是LADA患者主要易感单体型，其相对风险与T1DM类似， OR值分别为2.02 vs. 2.20与1.61 vs. 2.30。与T1DM有强相关的单体型DRB1*0301-DQA1*05-DQB1*0201 (DR3)与LADA也有显著相关性，其相对风险约为T1DM的一半(OR：2.65 vs. 4.84)。而与T1DM强易感有关的DRB1*0901-DQA1*05-DQB1*0201, DRB1*0301-DQA1*03-DQB1*0201与DRB1*0301-DQA1*03- DQB1*0303却未发现与LADA有相关性(Pc均＞0.05)。本研究发现的LADA易感单体型频率和风险显著不同于高加索人LADA易感单体型DR3 (31%~42%，OR=2.3~3.08)与DR4 (16.9%~38%, OR=2.6~3.2)。基因型DR3/DR3，DR3/DR9与DR9/DR9与T1DM易感性有显著相关性(Pc＜0.001)，其中仅DR9/DR9与LADA易感性有关(8.5%，OR=2.75，Pc＜0.01)，亦显著不同于高加索人LADA高危基因型DR3/DR4 (17.6%, OR=12.0)。本项目未发现非HLA基因IFIH1与TCF7L2对LADA有遗传易感作用。进一步发现老年LADA在临床表型与遗传背景上不同于青年LADA，具有更类似于T2DM的临床代谢与HLA遗传谱。本项目表明中国LADA患者HLA-DRB1-DQA1-DQB1位点遗传易感基因风险显著不同于经典T1DM及高加索人LADA。该研究为中国LADA高危人群筛选及疾病鉴别诊断提供了遗传学基础，对进一步理解LADA的病因学发病机制提供了新视角，为临床管理LADA患者提供了决策依据。