New Susceptibility Locus for Rheumatoid Arthritis Suggested by a Genome-Wide Linkage Study

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 18; pp. 10746 - 10750
• Main Authors: Cornelis, Francois, Faure, Sabine, Martinez, Maria, Jean-Francois Prud'homme, Fritz, Pierre, Dib, Colette, Alves, Helena, Barrera, Pilar, De Vries, Niek, Balsa, Alejandro, Pascual-Salcedo, Dora, Maenaut, Kristin, Westhovens, Rene, Migliorini, Paola, Tran, Tuyet-Hoa, Delaye, Arnaud, Prince, Nathalie, Lefevre, Caroline, Thomas, Gaelle, Poirier, Murielle, Soubigou, Stephane, Alibert, Olivier, Lasbleiz, Sandra, Fouix, Sylvaine, Bouchier, Christiane, Liote, Frederic, Loste, Marie-Noelle, Lepage, Virginia, Charron, Dominique, Gyapay, Gabor, Lopes-Vaz, Antonio, Kuntz, Daniel, Bardin, Thomas, Weissenbach, Jean
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01-09-1998; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Alleles; Arthritis; Arthritis, Rheumatoid - genetics; Autoimmune diseases; Biological Sciences; Chromosomes; Genetic Linkage; Genetic loci; Genetic Predisposition to Disease; Genetics; Genome; Genomes; Genotype; HLA antigens; HLA Antigens - genetics; Humans; Medical genetics; P values; Rheumatism; Rheumatology; Type 1 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• 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 (λ 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.