Endocrine Abstracts

The common autoimmune endocrinopathies are caused by susceptibility alleles at several genetic loci including MHC, CTLA4, PTPN22 and probably several others. Many of these susceptibility alleles are shared between several different autoimmune disorders including type 1 diabetes, autoimmune thyroid diseases and rheumatoid arthritis. In recent months a novel susceptibility locus was identified in the 5’ end of the Fc receptor-like 3 (FCRL3) gene in Japanese patients with rheumatoid arthritis, Graves’ disease and SLE. The putative susceptibility allele (FCRL3_3C), at position -169 relative to the transcription start site, was associated with a higher promoter activity and with increased NFκB promoter binding in gel-shift studies, suggesting a direct functional role.

We have examined a 4 marker FCRL3 haplotype, encompassing the markers reported to be associated with autoimmunity, FCRL3_3 to FCRL3_6, in UK subjects with autoimmune Addison’s disease (n=104), Graves’ disease (n=616) and in healthy controls (n=469). Genomic DNA was genotyped using a primer extension-MALDI-TOF assay (Sequenom) or by PCR-RFLP. Analysis was performed using haploview and unphased software.

There was tight linkage disequilibrium between the 4 markers studied with pairwise D’ values of between 0.93 and 1.0. Surprisingly, the putative susceptibility allele, FCRL3_3C, was present in a decreased number, of 37.4% of the Addison’s disease alleles, as compared to 47.8% of the control alleles; p=0.007; odds ratio 1.54 (5–95% 1.13 to 2.10). Alleles of the three other FCRL3 markers were also associated with Addison’s disease with p values ranging from 0.02 to 0.008. The four marker FCRL3 haplotype showed association with Addison’s disease with a global p value of 0.02 (unphased). In contrast, no marker showed association with Graves’ disease. These results confirm that FCRL3 is an autoimmune disease susceptibility locus in Caucasians too, but suggest the “disease” allele is other than the promoter -169 FCRL3_3C.