New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study

Abstract

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 (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 < 2.5⅐10 ؊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 antigenspecific 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.

Evidence for linkage to and association with type 1 diabetes at the 3q21 region in the Finnish population

“…7 This raises the possibility that a common autoimmune factor, involved in both T1D and RA etiology, is encoded by a gene located in this region, which would make our results relevant also for the mapping of RA genes.…”

Genetic analysis of multiplex rheumatoid arthritis families

“…21 Other studies have found a significant but weak association of a TCR␣ chain polymorphism with RA. 22 Recent studies indicate possible linkage of RA with several other non-MHC loci or genes, [23][24][25][26] but none have been independently confirmed. The current study represents our initial studies of a substantial collection of multiplex RA families.…”

Induction of arthritis in HLA–DR4–humanized and HLA–DQ8–humanized mice by human cartilage proteoglycan aggrecan but only in the presence of an appropriate (non‐MHC) genetic background

“…Among the genetic components, the major histocompatibility complex (MHC) is probably the most important predisposing factor for RA (2)(3)(4)(5), but the MHC alone is insufficient for disease induction (2,6,7). Recently, several non-MHC loci have been identified that contain genes that are likely to be involved in the disease mechanism (8)(9)(10)(11).…”

“…Although the MHC has the strongest effect on RA susceptibility, several non-MHC loci show linkage with the disease in studies of multicase families (8)(9)(10)(11)16). A general problem with genome-wide mapping studies, however, is the relatively weak linkage between the non-MHC loci and disease susceptibility because of the extremely high genetic variation within the human population (1).…”