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

Summary 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 ( ATXN 2/ SH 2B3, MAGI 3, BACH 2, TPO and KALRN ) as significantly associated with the presence of thyroid peroxidase autoantibodies ( TPOA bs), whereas several other loci showed suggestive association. Methods In this study, we investigated 16 single nucleotide polymorphisms ( SNP s) associated with TPOA bs 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 SNP s within/near HCP 5 (rs3094228, P  =   1·6 × 10 −12 , OR  = 1·88), MAGI 3 (rs1230666, P =  1·9 × 10 −5 , OR  = 1·51) and ATXN 2/ SH 2B3 (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 HCP 5 ( P =  0·0014, OR  = 1·50) and showed a suggestive difference for MAGI 3 ( P =  0·0035, OR  = 1·50) SNP s. 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 ATXN 2/ SH 2B3 locus with susceptibility to GD . Furthermore, we observed a novel significant association within the HLA region at a SNP located near HCP 5 and confirmed the association of the MAGI 3 locus with GD susceptibility. HCP 5 and MAGI 3 SNP s were further correlated with age of GD onset. Finally, we identified TPO as a new susceptibility locus for GO .