The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease.

BACKGROUND: Despite great progress, the genetic basis of Graves' disease (GD) remains poorly understood. Recently, a population-based genomewide association study (GWAS) identified five novel loci (ATXN2/SH2B3, MAGI3, BACH2, TPO and KALRN) as significantly associated with the presence of thyroid peroxidase autoantibodies (TPOAbs), whereas several other loci showed suggestive association. METHODS: In this study, we investigated 16 single nucleotide polymorphisms (SNPs) associated with TPOAbs for the association with susceptibility to and phenotype of GD in a cohort of 647 patients with GD and 769 controls from a Polish Caucasian population. RESULTS: SNPs within/near HCP5 (rs3094228, P = 1·6 × 10(-12) , OR = 1·88), MAGI3 (rs1230666, P = 1·9 × 10(-5) , OR = 1·51) and ATXN2/SH2B3 (rs653178, P = 0·0015, OR = 1·28) loci were significantly associated with susceptibility to GD. Allele frequencies differed significantly in subgroups of patients with GD stratified by age of GD onset for HCP5 (P = 0·0014, OR = 1·50) and showed a suggestive difference for MAGI3 (P = 0·0035, OR = 1·50) SNPs. Although rs11675434 located near TPO showed no association with GD susceptibility, it was significantly associated with the presence of clinically evident Graves' ophthalmopathy (GO, P = 5·2 × 10(-5) , OR = 1·64), and this effect was independent from smoking status, age of GD onset and gender. CONCLUSIONS: This is the first study showing an association of the ATXN2/SH2B3 locus with susceptibility to GD. Furthermore, we observed a novel significant association within the HLA region at a SNP located near HCP5 and confirmed the association of the MAGI3 locus with GD susceptibility. HCP5 and MAGI3 SNPs were further correlated with age of GD onset. Finally, we identified TPO as a new susceptibility locus for GO.