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The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease
Author(s) -
Kuś Aleksander,
Szymański Konrad,
Peeters Robin P.,
Miśkiewicz Piotr,
Porcu Eleonora,
Pistis Giorgio,
Sanna Serena,
Naitza Silvia,
Płoski Rafał,
Medici Marco,
Bednarczuk Tomasz
Publication year - 2015
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.12640
Subject(s) - single nucleotide polymorphism , snp , medicine , genome wide association study , graves' disease , locus (genetics) , allele , genetic predisposition , population , endocrinology , thyroid peroxidase , genetic association , thyroid , genetics , genotype , biology , disease , gene , environmental health
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 .