Association of FcGRIIa with Graves' disease: a potential role for dysregulated autoantibody clearance in disease onset/progression.

OBJECTIVE: Although autoantibody production is a key feature of autoimmunity, it is not known whether variation in autoantibody production and clearance pathways is involved in disease susceptibility. The Fc Gamma Receptor IIa (FcGRIIa) molecule is involved in the clearance of autoantibodies and a functional single nucleotide polymorphism (SNP), rs1801274, which has been shown to alter autoantibody clearance, has been associated with a number of autoimmune diseases (AIDs) including systemic lupus erythematosus and type 1 diabetes. This study aimed to determine whether FcGRIIa is associated with Graves' disease (GD) in the UK Caucasian population by Tag SNP screening common polymorphisms within the FcGRIIa region. DESIGN: A case control association study investigating nine Tag SNPs within FcGRIIa, which captured the majority of known common variation within this gene region. PATIENTS: A dataset comprising 2504 UK Caucasian GD patients and 2784 geographically matched controls taken from the 1958 British Birth cohort. MEASUREMENTS: We used the chi(2)-test to investigate association between the Tag SNPs and GD. RESULTS: Association between the rs1801274 (P = 0.003, OR = 1.12 [95% CI = 1.03-1.22] and rs6427598 (P = 0.012, OR = 0.90 [95% CI = 0.83-0.98]) SNPs and GD was observed. No other SNPs showed association with GD. No associations were seen between any of the SNPs investigated and specific GD clinical phenotypes. CONCLUSIONS: This study suggests that variation in FcGRIIa predisposes to GD and further supports the role of FcGRIIa as a susceptibility locus for AIDs in general.

Confirmation of association of chromosome 5q31-33 with United Kingdom Caucasian Graves' disease.

BACKGROUND: Previous genome-wide microsatellite screening in Graves' disease (GD) has suggested several regions of linkage to disease. Although replication has been inconsistent, some regions such as chromosome 5q31-33 have been associated with several Oriental GD patient cohorts. Recently, two studies have reported association of single-nucleotide polymorphism (SNP) rs31480 in interleukin 3 (IL-3) and the rs1368408 and SNP75 (-623 approximately -622 AG/-T) SNPs in secretoglobulin family 3a member 2 (SCGB3A2) with GD and suggested that this may account for linkage to the 5q31-33 region in Oriental GD datasets. We sought to confirm this association in a large Caucasian U.K. GD cohort. METHODS: The rs31480 SNP was shown to tag all known common variations in IL-3 and the rs1368408 SNP was shown to tag all common variations in SCGB3A2. The SCGB3A2 SNP75 was found to be rare in the U.K. Caucasian population and, therefore, was not screened. We genotyped rs31480 and rs1368408 and performed a case-control association study in 2504 GD cases and 2688 controls from the U.K. RESULTS: Association between the SCGB3A2 rs1368408 SNP and GD was detected (p = 0.007, odds ratio = 1.18, 95% confidence intervals = 1.05-1.33). No association between the IL-3 rs31804 SNP and U.K. Caucasian GD patients was observed. CONCLUSIONS: These data suggest that chromosome 5q31-q33 contains a susceptibility locus for Caucasian GD patients as well as Oriental GD patients. Although association was detected between SCGB3A2 and U.K. Caucasian GD subjects, the size of effect was smaller than that seen in the Oriental population (odds ratio = 1.28-1.73). Fine mapping within this region will be required to determine the exact location of the etiological variants present within this region for both Caucasian and Oriental GD patients.