A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic etiology. Herein we identify a single-nucleotide polymorphism (SNP) in the promoter region of FcRH3, a member of the Fc receptor homolog family, that is associated with RA susceptibility (OR=2. 15, P=0.00000085). This polymorphism alters the binding affinity of nuclear factor-κB and regulates NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFcRH3 expression. High FcRH3 expression on B-cells and augmented autoantibody production were observed in individuals with the disease-susceptible genotype. Associations were also found between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FcRH3 may thus play a pivotal role in autoimmunity.Rheumatoid arthritis represents one of the most common autoimmune diseases, and is characterized by inflammation of synovial tissue and joint destruction. Although the disease is believed to result from a combination of genetic and environmental factors, the complete etiology of RA has not yet been clarified 1 . While specific haplotypes of human leukocyte antigen (HLA)-DRB1, usually referred to as shared-epitope (SE) sequences 2 , have been repeatedly reported as conferring RA-susceptibility 3,4 , other genetic components are also involved in the pathogenesis of RA 5 . This combination of HLA haplotypes and non-HLA genes accounting for disease susceptibility is also seen in other autoimmune diseases 6-8 . In autoimmune thyroid disease (AITD), for instance, studies have consistently shown that the HLA-DR3 haplotype is associated with disease risk, in addition to a functional haplotype of a non-HLA gene, CTLA4, that has recently been associated with AITD susceptibility 9 .Identification of non-HLA genes associated with RA susceptibility and other autoimmunities seems difficult, due to the low relative risk of disease resulting from these non-HLA genes compared with the strong relative risk from disease-associated HLA haplotypes. In a search for non-HLA determinants of disease susceptibility, whole genome studies have been conducted for both human autoimmune diseases and experimental animal models. These studies have revealed non-random clustering of susceptibility loci for clinically distinct diseases 8,10 . This overlapping of susceptibility loci for multiple autoimmunities suggests the existence of common susceptibility genes in those regions. Intense studies of loci-clustering regions has revealed genes commonly associated with multiple autoimmune diseases, such as CTLA4 on 2q33 (ref. and Idd17 (ref. 25)). Although 1q21-23 is a strong candidate region for RA susceptible genes, as above mentioned, the association of classical FcγRs with disease susceptibility remains controvertial 26,27 . The present study focused on the 1q21-23 region to identify RA-associated genes in Japanese subjects using linkage disequilibrium (LD) mapping. RESULTS Case-control study by SNP-based LD-mapping in 1q21-23To evaluate the extent of association, we a...

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

“…18,19 Interestingly, FCRL3, a member of this family in humans, is associated with RA and other autoimmune conditions, including lupus. 20 We are currently investigating whether one or both of these genes present allelic differences between NZW and B6. If it were the case, it would be possible that these genes could indirectly regulate Fcrg2b on GC B cells.…”

Association of NFKB1 −94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease

“…19 Interestingly, FCRL3 has been recently associated with susceptibility to GD. 9,20 A different (CA) repeat polymorphism located in the 3 0 region of NFKB1 has been reported to be associated with T1D but subsequent studies were unable to confirm this finding. [21][22][23] In this study, the frequency of the D allele in control populations were similar to those observed in other Caucasian populations, as reported by Karban (39%).…”

Two-stage case–control association study of polymorphisms in rheumatoid arthritis susceptibility genes with schizophrenia

“…In that study, an SNP (runx1) of RUNX1 on 21q22.3 was also associated with RA. Kochi et al 12 showed an association of a functional SNP at position À169 (fcrh3_3) in the promoter region of Fc receptor-like 3 (FCRL3) on 1q21-23 with RA. This SNP altered the binding affinity for nuclear factor-kB and regulated the expression of FCRL3 mRNA.…”