采用MHC区域捕获测序技术深入探寻IgA肾病的致病基因

Previous GWAS studies have identified MHC region as the susceptibility loci in IgA nephropaty (IgAN). However, because of the highly polymorphic nature of this region and the extensive linkage disequilibrium (LD) that exists, there has been a remarkable lack of progress in identifying the causal variants underlying these associations, thus hindering elucidation of the molecular mechanisms involved. On the basis of our previous work, (1) we perform the MHC region capture and next generation sequencing, to obtain the whole spectrum of the genetic variants in the MHC region, including common variants, rare variants, structural variants, high solution HLA genotyping and amino acid variants, to identify the specific susceptibility loci of IgAN. (2) using “Chinese Han MHC dataset” as the reference panel, perform the imputation analysis of the GWAS data for IgAN, to validate the sequence result; selecting the significant SNPs and validating in a large separate cohort, to identify more novel susceptibility genes for IgAN. (3) Studying the correlation of the susceptibility genes and the clinical manifestation, pathological pattern, prognosis and response to treatment of IgAN patients, to detect the susceptibility genes for early prediction of the clinical outcomes and response to treatment, to explore the biological markers of early warning for IgAN and guide the individualized treatment. （4）Functional study of the susceptibility genes, to identify the causal gene of IgAN, and discover the new target for the precise treatment of IgAN.

既往多个IgA肾病GWAS均发现MHC区域与其发病相关。而由于MHC区域高度的遗传多态性和连锁不平衡，很难鉴定MHC区域的致病变异。本项目拟在前期工作基础上，全面系统了解IgA肾病MHC区域的遗传信息，包括：①采用MHC区域捕获及高通量测序方法，了解IgA肾病患者MHC区域的遗传变异图谱，包括基因变异、结构变异、高精度HLA基因型及氨基酸序列改变等，从而发现IgA肾病特有的易感位点。②以中国汉族人群MHC数据库为参考，对已有GWAS数据进行imputation，以验证靶向测序结果；并对发现的差异位点在大样本群中进行验证，从而发现IgA肾病新的易感基因。③将易感基因与IgA肾病患者的临床表现、病理类型、治疗反应及临床结局进行相关分析，寻找可以早期预测IgA肾病发病及预警治疗反应及临床结局的生物学标记；④开展相关基因的功能学研究，以探寻IgA肾病的致病基因，为特异性IgA肾病治疗寻找新的靶点。

本项目在前期中国汉族人群GWAS工作基础上，结合欧美高加索人群IgAN的GWAS数据，对IgAN患者和对照组的MHC区域进行Meta-GWAS和imputation分析，发现了MHC区域的三个新的独立易感信号，并进一步证实了IgA肾病存在种族和地域的差异。我们还对GWAS发现的易感基因开展基因多态性研究，其中对FCRL3、ITGAX-ITGAM和ST6GALT1等基因的深入研究，发现这些基因的变异及表达水平与IgA肾病的易感性及临床表型密切相关。我们还发现CFB基因为IgA肾病与IBD的共同易感基因，揭示了不同免疫性疾病之间的基因共效性。该项目对于明确IgA肾病的遗传发病机制，进一步探索IgA肾病特异性治疗方法及干预新靶点，具有重要的科学意义和实用价值。

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