Endocrine Abstracts

Identifying the pathogenic pathways involved in complex diseases such as Graves’ disease (GD) has proved challenging. Although several genetic risk factors, including the HLA class II region, CTLA4, PTPN22 and CD25, encode molecules playing key roles in antigen presentation and controlling T cell recognition/signalling, the identification of novel susceptibility loci has the potential to provide further insights into disease pathogenesis. Recently genome wide screening confirmed association of FCRL3 with GD, with Tag single nucleotide polymorphism (SNP) screening of FCRL3 detecting association of four SNPs with disease. During the same genome screen, association of three SNPs within neighboring FCRL5 was also detected. A single Tag SNP was employed to capture the common variation resulting from all three SNPs and association was confirmed in an expanded dataset. Twelve further Tag SNPs were then employed to screen the remainder of the common variation within FCRL5 using a large UK Caucasian cohort (2504 GD patients and 2784 controls). All cases and controls gave informed written consent and the project was approved by the local ethics committees. Of the 12 SNPs screened, three additional Tag SNPs (P=0.015–0.001, OR=1.11–1.16) were associated with GD. Susceptibility alleles of two of the four Tag SNPs were also associated with goitre (P=0.034–0.020), suggesting a potential role for FCRL5 in goitre development. Due to the close proximity of FCRL5 to FCRL3, linkage disequilibrium (LD) was investigated but was not detected suggesting an independent effect on susceptibility for each locus. As both FCRL5 and FCRL3 are key molecules in B cell signalling, our results provide further evidence of a role for disrupted B cell signalling in GD pathogenesis. Further work is now warranted to determine the location and functional consequences of the etiological variant/s present in the FCRL region.