中国人群麻风全基因组关联研究

        麻风（Leprosy）是由于麻风分支杆菌感染易感个体后，经过一定的潜伏期，选择性的侵犯皮肤和外周神经、晚期可致残的慢性传染病，严重危害人类健康。资料表明，全球每年仍有20余万新报告病例，中国每年新报告病例近2000例。

        2009年，由安徽医科大学皮肤病研究所张学军教授领衔的研究团队联合山东省医科院所属的皮肤病性病防治研究所张福仁研究员率领的研究团队采用全基因组关联研究（GWAS）方法，使用Illumina Human 610-Quad全基因组SNP分型芯片对中国人群706例麻风患者和1225例正常对照进行基因分型，经过严格的数据质控和统计分析，分别在另外三个独立人群（其中二个独立人群来自于中国汉族，另外1个独立人群来自中国少数名族，共计3254例麻风病例和5955例正常对照）对93个的SNPs进行验证研究，发现了7个麻风病的易感基因：CCDC122 、C13or f 31 、NOD2 、T N FS F15 、H L A-DR 、RI PK2 和L RRK 2。上述易感基因均参与机体从识别到抗原递呈处理、细胞因子调节及免疫细胞转导等炎症和免疫过程，这些基因的变异与麻风发病机制密切相关。其中，发现多菌性麻风易感基因C13or f 31 、L RRK2 、NOD2 、RI PK2 ,５个易感基因位于NOD２介导的信号通路上， 提示该信号通路在麻风发病中具有重要作用, 为揭示疾病发病机制提供了重要契机。

        这一研究成果的论文由国际著名学术期刊《新英格兰医学杂志》在线发表，该研究是世界范围内首个完成的麻风易感基因的GWAS研究，发现了与麻风发病机制密切相关的7个易感基因位点,标志着中国麻风病易感基因研究已经处于世界领先水平,对深入了解麻风的发病机制将起到积极的推动作用，也为疾病预警、遗传咨询、临床医疗、新药开发等提供了科学依据。

原文信息：

Genomewide association study of leprosy. N Engl J Med. 2009;361(27):2609-18.

摘要：

BACKGROUND:

The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression.

METHODS:

We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary).

RESULTS:

We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy.

CONCLUSIONS:

Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprosy.