Lettre Guillaume, Rioux John D
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Hum Mol Genet. 2008 Oct 15;17(R2):R116-21. doi: 10.1093/hmg/ddn246.
Autoimmune diseases occur when an individual's own immune system attacks and destroys his or her healthy cells and tissues. Although it is clear that environmental stimuli can predispose someone to develop autoimmune diseases, twin- and family-based studies have shown that genetic factors also play an important role in modifying disease risk. Because many of these diseases are relatively common (prevalence in European-derived populations: 0.01-1%) and exhibit a complex mode of inheritance, many DNA sequence variants with modest effect on disease risk contribute to the genetic burden. Recently, the completion of the HapMap project, together with the development of new genotyping technologies, has given human geneticists the tools necessary to comprehensively, and in an unbiased manner, search our genome for DNA polymorphisms associated with many autoimmune diseases. Here we review recent progress made in the identification of genetic risk factors for celiac disease, Crohn's disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and type-1 diabetes using genome-wide association studies (GWAS). Strikingly, GWAS have increased the number of genetic risk variants associated with these autoimmune diseases from 15 before 2006 to 68 now. We summarize what this new genetic landscape teaches us in terms of the pathogenesis of these diseases, and highlight some of the outstanding challenges ahead. Finally, we open a discussion on ways to best maximize the impact of these genetic discoveries where it matters the most, that is for autoimmune disease patients.
当个体自身的免疫系统攻击并破坏其健康细胞和组织时，自身免疫性疾病就会发生。虽然环境刺激会使某人易患自身免疫性疾病这一点很明确，但基于双胞胎和家族的研究表明，遗传因素在改变疾病风险方面也起着重要作用。由于这些疾病中有许多相对常见（在欧洲裔人群中的患病率为0.01 - 1%），并且呈现出复杂的遗传模式，许多对疾病风险有适度影响的DNA序列变异会导致遗传负担。最近，国际人类基因组单体型图计划（HapMap计划）的完成，以及新基因分型技术的发展，为人类遗传学家提供了必要的工具，以便全面且无偏差地在我们的基因组中搜索与多种自身免疫性疾病相关的DNA多态性。在此，我们回顾了利用全基因组关联研究（GWAS）在乳糜泻、克罗恩病、多发性硬化症、类风湿性关节炎、系统性红斑狼疮和1型糖尿病遗传风险因素识别方面取得的最新进展。引人注目的是，GWAS已将与这些自身免疫性疾病相关的遗传风险变异数量从2006年前的15个增加到了现在的68个。我们总结了这一新的遗传格局在这些疾病发病机制方面给我们的启示，并强调了一些未来面临的突出挑战。最后，我们展开讨论，探讨如何在最重要的方面，即对自身免疫性疾病患者，最大程度地发挥这些遗传发现的影响。
