NALP1 in vitiligo-associated multiple autoimmune disease
NALP1 in vitiligo-associated multiple autoimmune disease
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DOI：
10.1056/nejmoa061592
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发表时间：
2007-03-22
影响因子：
158.5
通讯作者：
Spritz, Richard A.
中科院分区：
文献类型：
--
作者：
Jin, Ying;Mailloux, Christina M.;Spritz, Richard A.
背景：自身免疫性和自身炎症性疾病涉及遗传危险因素和环境因素之间的相互作用。我们搜索了染色体17p13上的一个基因，该基因与一组流行病学相关的自身免疫性和自体炎性疾病有关。该组包括泛发性白癜风、自身免疫性甲状腺疾病、成人隐匿性自身免疫性糖尿病、类风湿性关节炎、银屑病、恶性贫血、系统性红斑狼疮和阿迪森病的各种组合。方法：我们检测了177个跨越17p13连锁高峰的单核苷酸多态(SNPs)与疾病的关联，并确定了一个强有力的候选基因。然后，我们对该基因内部和周围的DNA进行了测序，以确定其他SNPs。我们利用其中一些额外的SNPs进行了第二轮关联测试，从而详细地阐明了该基因及其扩展的启动子区域与疾病的关联。结果：关联分析结果表明，我们确定了一个候选基因NALP1，该基因编码Nacht-Leucine-rich-Repeat Protein 1，Nacht-Leucine-Repeat Protein 1，一种天然免疫系统的调节因子。使用来自受影响家庭的DNA和NALP1及其周围的额外SNPs的精细关联图谱显示，特定变异与单独的白癜风、延长的自身免疫性和自身炎症性疾病表型或两者都有关联。对NALP1基因SNPs的条件Logistic回归分析表明，至少有两个变异对疾病的风险有独立作用。结论：NALP1区域的DNA序列变异与几种流行病学相关的自身免疫性和自身炎症性疾病的风险有关，提示先天免疫系统参与了这些疾病的发病机制。
Background: Autoimmune and autoinflammatory diseases involve interactions between genetic risk factors and environmental triggers. We searched for a gene on chromosome 17p13 that contributes to a group of epidemiologically associated autoimmune and autoinflammatory diseases. The group includes various combinations of generalized vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease.Methods: We tested 177 single-nucleotide polymorphisms (SNPs) spanning the 17p13 linkage peak for association with disease and identified a strong candidate gene. We then sequenced DNA in and around the gene to identify additional SNPs. We carried out a second round of tests of association using some of these additional SNPs, thus elucidating the association with disease in the gene and its extended promoter region in fine detail.Results: Association analyses resulted in our identifying as a candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune system. Fine-scale association mapping with the use of DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. Conditional logistic-regression analysis of NALP1 SNPs indicated that at least two variants contribute independently to the risk of disease.Conclusions: DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders.