New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study
New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study
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DOI：
10.1073/pnas.95.18.10746
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发表时间：
1998-09-01
影响因子：
11.1
通讯作者：
Weissenbach, J
中科院分区：
文献类型：
--
作者：
Cornelis, F;Faure, S;Weissenbach, J
类风湿性关节炎（RA）是最常见的自身免疫性疾病，在家族中与其他自身免疫性疾病相关，包括胰岛素依赖型糖尿病（IDDM）。家族聚集（λ s = 5）、双胞胎研究和分离分析表明其遗传成分。HLA是已知的唯一易感性位点，估计占这一成分的三分之一。本文的目的是鉴定新的RA位点。对来自97个核心家庭的114对欧洲高加索RA sib对进行了基因组扫描。只有HLA有显著的连锁性（P < 2.5 10(-5)），其他14个地区的19个标记无显著连锁性（P < 0.05）。与IDDM相关的四个基因座可能与这些区域重叠：假定的IDDM6、IDDM9、IDDM13和DXS998基因座。在RA基因组扫描中分别由标记D18S68-D18S61-D18S469 （18q22-23）和D3S1267 （3q13）定义的前两个候选区域，在164个核心家族的194对RA sib中进行了研究。仅与第3号染色体连锁的支持度显著延长（P = 0.002）。对所有261个家族的分析提供了P = 0.001的连锁证据，表明该假定的RA位点与HLA之间存在相互作用。该位点可能占RA遗传成分的16%。候选基因包括编码CD80和CD86的基因，它们是参与抗原特异性T细胞识别的分子。总之，在RA高加索家族的第一次基因组扫描中发现了14个候选区域，其中一个区域得到了第二组家族研究的进一步支持。
Rheumatoid arthritis (RA), the most common autoimmune disease, is associated in families with other autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). Its genetic component has been suggested by familial aggregation (lambda s = 5), twin studies, and segregation analysis. HLA, which is the only susceptibility locus known, has been estimated to account for one-third of this component. The aim of this paper was to identify new RA loci. A genome scan was performed with 114 European Caucasian RA sib pairs from 97 nuclear families. Linkage was significant only for HLA (P < 2.5 10(-5)) and nominal for 19 markers in 14 other regions (P < 0.05). Four of the loci implicated in IDDM potentially overlap with these regions: the putative IDDM6, IDDM9, IDDM13, and DXS998 loci. The first two of these candidate regions, defined in the RA genome scan by the markers D18S68-D18S61-D18S469 (18q22-23) and D3S1267 (3q13), respectively, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0.001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA. Candidate genes include those coding for CD80 and CD86, molecules involved in antigen-specific T cell recognition. In conclusion, this first genome scan in RA Caucasian families revealed 14 candidate regions, one of which was supported further by the study of a second set of families.