Cornélis F, Fauré S, Martinez M, Prud'homme J F, Fritz P, Dib C, Alves H, Barrera P, de Vries N, Balsa A, Pascual-Salcedo D, Maenaut K, Westhovens R, Migliorini P, Tran T H, Delaye A, Prince N, Lefevre C, Thomas G, Poirier M, Soubigou S, Alibert O, Lasbleiz S, Fouix S, Bouchier C, Lioté F, Loste M N, Lepage V, Charron D, Gyapay G, Lopes-Vaz A, Kuntz D, Bardin T, Weissenbach J
Pôle Génétique des Maladies Auto-immunes, Laboratoire de Radiologie Expérimentale et de Physiopathologie Articulaire, Centre Viggo-Petersen, Hôpital Lariboisière, 75010 Paris, France.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10746-50. doi: 10.1073/pnas.95.18.10746.
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 (lambdas = 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.
类风湿关节炎（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）。家族聚集性（λ=5）、双胞胎研究和分离分析提示其存在遗传成分。已知唯一的易感基因座HLA估计占该成分的三分之一。本文旨在鉴定新的RA基因座。对来自97个核心家庭的114对欧洲白种人RA同胞对进行了全基因组扫描。仅HLA存在显著连锁（P<2.5×10⁻⁵）；其他14个区域的19个标记存在名义连锁（P<0.05）。与IDDM相关的4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全基因组扫描中，这两个候选区域分别由标记D18S68-D18S61-D18S469（18q22-23）和D3S1267（3q13）定义，对来自164个核心家庭另外194对RA同胞对进行了研究。仅对3号染色体连锁的支持显著增强（P=0.002）。对所有261个家庭的分析提供了P=0.001的连锁证据，并提示该假定的RA基因座与HLA之间存在相互作用。该基因座可解释RA遗传成分的16%。候选基因包括编码CD80和CD86的基因，这些分子参与抗原特异性T细胞识别。总之，对RA白种人家庭的首次全基因组扫描揭示了14个候选区域，其中一个区域在另一组家庭的研究中得到了进一步支持。
