Identification of the gene loci that predispose to rheumatoid arthritis.

Abstract

We have searched the human genome for genes that predispose to rheumatoid arthritis (RA) using fluorescence-based microsatellite marker analysis and affected sib-pair linkage study. A panel of 41 Japanese families, each with at least two affected siblings, was typed for genome-wide 358 polymorphic microsatellite marker loci. Markers were amplified by the PCR using fluorescence-tagged primers and sized based on the difference of CA repeats on DNA. Linkage analysis was made using maximum lod score (MLS). The MLS for D1S214 and D8S556 was 3.27 and 3.33, while the MLS for the HLA-DRB1 region was<3.0. According to detailed analysis by single-point analysis using MAPMAKER/SIBS, the MLS for D1S253 and D1S214 was 3.77 and 3.58. The MLS by multipoint analysis was 6.13 for D1S253. The MLS for D8S556 by single-point analysis was 4.20. The MLS for DXS1232 was 2.35 by single-point analysis, whereas the MLS for the region 2 cM right to DXS1232 and the region between DXS1227 and DXS1200 was 3.03 and 2.93 by multi-point analysis. Three principal chromosome regions of linkage, D1S253/214, D8S556 and DXS1232, have been identified which we call RA1, RA2 and RA3 for RA disease loci.

Genetic analysis of multiplex rheumatoid arthritis families

“…Other non-MHC candidate regions including the IDDM9 region of chromosome 3 and the proximal region of human chromosome 1 suggested in other preliminary studies, 23,25 were not confirmed in the current study. Similarly, these studies did not find a significant linkage for candidate loci suggested in the current study.…”

“…Similarly, these studies did not find a significant linkage for candidate loci suggested in the current study. Another putative susceptibility locus at Xq27 recently suggested 25 was not examined in the current study. Of additional note, another report 33 has provided some support for our initial studies suggesting linkage with CYP19 at 15q15.…”

“…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.…”

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

“…Chromosome region 1q31 has been implicated in linkage studies in lupus and multiple sclerosis (22)(23)(24). Multiple investigations have suggested linkage for chromosome region 1p36 in lupus (24)(25)(26), celiac disease (27), inflammatory bowel disease (28), and RA (29,30). This region was delineated further in adult RA using a case-control association design of single-nucleotide polymorphisms, resulting in a functional haplotype associated with RA that includes the gene PADI4 (31).…”

Death receptor 3 (DR3) gene duplication in a chromosome region 1p36.3: gene duplication is more prevalent in rheumatoid arthritis

“…3,4 We previously assigned three principal chromosome regions of linkage, D1S253/214, D8S556 and DXS1232, with maximum lod scores (MLSs) 3.77/6.13, 4.20/1.14 and 2.35/3.03, respectively, by single/multi-point analyses. 5 The death receptor 3 (DR3) gene was mapped in the vicinity of D1S214/ 253 by the GeneBridge 4.0 radiation hybrid panel. Based on the EBI/Sanger Institute ENSEMBL database, D1S214 and D1S253 reside at 6.7 and 6.0 Mb, respectively, and DR3 at 6.2 Mb of chromosome 1p36.…”