Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection:: the PTPN22 620W allele associates with multiple autoimmune phenotypes
Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection:: the PTPN22 620W allele associates with multiple autoimmune phenotypes
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DOI：
10.1086/429096
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发表时间：
2005-04-01
影响因子：
9.8
通讯作者：
Gregersen, PK
中科院分区：
文献类型：
--
作者：
Criswell, LA;Pfeiffer, KA;Gregersen, PK
自身免疫性疾病是一组不同的表型，具有重叠的特征和家族聚集的趋势。这些疾病很可能与共同的潜在基因有关。直到最近，除了一些常见的人类白细胞抗原II类基因外，还没有发现明确与多种不同自身免疫性疾病相关的特定等位基因。在这项研究中，我们描述了由多重自身免疫性疾病遗传学协会（MADGC）组装的265个多重家族的独特集合。这些家族中至少有九种“核心”自身免疫性疾病中的两种。这些核心疾病包括类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、1型糖尿病（T1D）、多发性硬化症（MS）、自身免疫性甲状腺疾病（桥本甲状腺炎或Graves病）、幼年类风湿性关节炎、炎症性肠病（克罗恩病或溃疡性结肠炎）、牛皮癣和原发性干燥综合征。我们报道了最近描述的细胞内酪氨酸磷酸酶（PTPN22）的功能单核苷酸多态性（rs2476601，编码R620W）赋予这些家族中四种不同自身免疫表型的风险：T1D， RA， SLE和桥本甲状腺炎。MS未显示与PTPN22风险等位基因相关。这些发现提示了一些（但不是全部）自身免疫性疾病的共同潜在病因通路，并且提示MS可能具有不同于RA、SLE和T1D的发病机制。科学界可以获得MADGC家族的DNA和临床数据；这些数据将为解剖复杂的遗传因素提供宝贵的资源，这些遗传因素是各种自身免疫表型的基础。
Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles - aside from a few common human leukocyte antigen class II genes - had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium ( MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis ( RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis ( MS), autoimmune thyroid disease ( Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease ( Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.