Functional SNPs involved in NF-κB signalling and binding pathways and their contribution to the pathogenesis of graves disease
MJ Simmonds, JM Heward, JD Carr-Smith, H Foxall, JA Franklyn & SCL Gough
The HLA class II region, CTLA-4 and PTPN22, have been consistently associated with autoimmune disease (AID). Recently, three DNA variants, two of which (M55V and 001Msp) are present in NF-κB inhibitors SUMO-4 and MAP3K7IP2, and one of which (fcrl3_3) modulates NF-κB binding and production of the B cell surface molecule FCRL3, have been reported to be associated with a number of AIDs. The aim of this study was to investigate genetic variation within this important signalling pathway in a large UK Caucasian Graves disease (GD) dataset. In total 1056 patients with GD and 864 control subjects were genotyped for the M55V, 001Msp and fcrl3_3 single nucleotide polymorphisms (SNPs). All subjects gave informed written consent, and the project was approved by the local ethics committee. Association was found between GD and 001Msp (OR=1.19, 95% CI =1.03–1.37) and fcrl3_3 (OR =1.17, 95% CI =1.02–1.34), although at a significantly lower level than previously reported. No association with disease was found at M55V. No evidence for an interaction with the previously established HLA class II, CTLA-4 and PTPN22 GD associated alleles was observed. The 001Msp SNP was however, found to be associated with thyroid autoantibody status (OR=1.43, 95% CI =1.06–1.91). Functional evidence suggests that 001Msp and fcrl3_3 can cause changes in B cell signalling and activation pathways that could account for their association with GD. Further replication in independent datasets and fine mapping of the surrounding gene regions is now needed to confirm the magnitude of the effect and location of the etiological variant(s) present within these gene regions.