Analysis of the Fc receptor-like-3 (FCRL3) locus in caucasians with autoimmune disorders suggests a complex pattern of disease association

Context: A four- marker haplotype in the 5' region of the Fc receptorlike 3 gene ( markers FCRL3_3 to FCRL3_6) has been identified recently as contributing to rheumatoid arthritis ( RA) susceptibility in the Japanese population. The promoter FCRL3_3*C allele also showed significant association with autoimmune thyroid disease and systemic lupus erythematosus. These findings raise the possibility that this locus may influence autoimmune disease susceptibility across many populations. Patients and Design: We analyzed the same four 5' FCRL3 single nucleotide polymorphism markers, together with three additional exonic single nucleotide polymorphisms in the FCRL3 gene, in cohorts of white Caucasians with Graves' disease ( n = 625), type 1 diabetes ( n = 279), autoimmune Addison's disease ( AAD; n = 200), andRA( n = 769). Healthy controls from the United Kingdom ( n = 490) and New Zealand ( n = 593) were used. Results: Six of the seven FCRL3 markers showed association with AAD ( P = 0.005 - 0.0001), with maximum evidence at the FCRL3_ 3*T. allele [ P([corrected]) = 0.0008; odds ratio ( OR), 1.61; 5 - 95% confidence intervals ( CIs), 1.26 - 2.05]. The most common seven- marker FCRL3 haplotype ( TGGGAAA) was also found to be significantly associated with AAD ( P([corrected]) = 1.1 x 10(-4); OR, 1.71; 5 - 95% CIs, 1.33 - 2.18). There was nominal evidence for allelic association at the marker FCRL3_8 in Graves' disease ( OR, 1.50; 5 - 95% CIs, 1.06 - 2.13) and at FCRL3_9 with RA ( OR, 1.25; 5 - 95% CIs, 1.01 - 1.54). Conclusions: The FCRL3 haplotype that is associated with AAD in Caucasians appears to be protective for autoimmune diseases in the Japanese population, demonstrating that this haplotype is unlikely to contain a single primary etiological allele for autoimmunity. Our observations suggest that the susceptibility to autoimmunity at the FCRL3 locus is more complex than initially thought and may extend either side of the currently associated region to include the adjacent FCRL2 gene.