TY - JOUR
T1 - Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.
JF - PLoS Genet
Y1 - 2014
A1 - Medici, Marco
A1 - Porcu, Eleonora
A1 - Pistis, Giorgio
A1 - Teumer, Alexander
A1 - Brown, Suzanne J
A1 - Jensen, Richard A
A1 - Rawal, Rajesh
A1 - Roef, Greet L
A1 - Plantinga, Theo S
A1 - Vermeulen, Sita H
A1 - Lahti, Jari
A1 - Simmonds, Matthew J
A1 - Husemoen, Lise Lotte N
A1 - Freathy, Rachel M
A1 - Shields, Beverley M
A1 - Pietzner, Diana
A1 - Nagy, Rebecca
A1 - Broer, Linda
A1 - Chaker, Layal
A1 - Korevaar, Tim I M
A1 - Plia, Maria Grazia
A1 - Sala, Cinzia
A1 - Völker, Uwe
A1 - Richards, J Brent
A1 - Sweep, Fred C
A1 - Gieger, Christian
A1 - Corre, Tanguy
A1 - Kajantie, Eero
A1 - Thuesen, Betina
A1 - Taes, Youri E
A1 - Visser, W Edward
A1 - Hattersley, Andrew T
A1 - Kratzsch, Jürgen
A1 - Hamilton, Alexander
A1 - Li, Wei
A1 - Homuth, Georg
A1 - Lobina, Monia
A1 - Mariotti, Stefano
A1 - Soranzo, Nicole
A1 - Cocca, Massimiliano
A1 - Nauck, Matthias
A1 - Spielhagen, Christin
A1 - Ross, Alec
A1 - Arnold, Alice
A1 - van de Bunt, Martijn
A1 - Liyanarachchi, Sandya
A1 - Heier, Margit
A1 - Grabe, Hans Jörgen
A1 - Masciullo, Corrado
A1 - Galesloot, Tessel E
A1 - Lim, Ee M
A1 - Reischl, Eva
A1 - Leedman, Peter J
A1 - Lai, Sandra
A1 - Delitala, Alessandro
A1 - Bremner, Alexandra P
A1 - Philips, David I W
A1 - Beilby, John P
A1 - Mulas, Antonella
A1 - Vocale, Matteo
A1 - Abecasis, Goncalo
A1 - Forsen, Tom
A1 - James, Alan
A1 - Widen, Elisabeth
A1 - Hui, Jennie
A1 - Prokisch, Holger
A1 - Rietzschel, Ernst E
A1 - Palotie, Aarno
A1 - Feddema, Peter
A1 - Fletcher, Stephen J
A1 - Schramm, Katharina
A1 - Rotter, Jerome I
A1 - Kluttig, Alexander
A1 - Radke, Dörte
A1 - Traglia, Michela
A1 - Surdulescu, Gabriela L
A1 - He, Huiling
A1 - Franklyn, Jayne A
A1 - Tiller, Daniel
A1 - Vaidya, Bijay
A1 - De Meyer, Tim
A1 - Jørgensen, Torben
A1 - Eriksson, Johan G
A1 - O'Leary, Peter C
A1 - Wichmann, Eric
A1 - Hermus, Ad R
A1 - Psaty, Bruce M
A1 - Ittermann, Till
A1 - Hofman, Albert
A1 - Bosi, Emanuele
A1 - Schlessinger, David
A1 - Wallaschofski, Henri
A1 - Pirastu, Nicola
A1 - Aulchenko, Yurii S
A1 - de la Chapelle, Albert
A1 - Netea-Maier, Romana T
A1 - Gough, Stephen C L
A1 - Meyer Zu Schwabedissen, Henriette
A1 - Frayling, Timothy M
A1 - Kaufman, Jean-Marc
A1 - Linneberg, Allan
A1 - Räikkönen, Katri
A1 - Smit, Johannes W A
A1 - Kiemeney, Lambertus A
A1 - Rivadeneira, Fernando
A1 - Uitterlinden, André G
A1 - Walsh, John P
A1 - Meisinger, Christa
A1 - den Heijer, Martin
A1 - Visser, Theo J
A1 - Spector, Timothy D
A1 - Wilson, Scott G
A1 - Völzke, Henry
A1 - Cappola, Anne
A1 - Toniolo, Daniela
A1 - Sanna, Serena
A1 - Naitza, Silvia
A1 - Peeters, Robin P
KW - Autoantibodies
KW - Genetic Loci
KW - Genome-Wide Association Study
KW - Graves Disease
KW - Hashimoto Disease
KW - Humans
KW - Iodide Peroxidase
KW - Risk Factors
KW - Thyroiditis, Autoimmune
KW - Thyrotropin
AB - Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

VL - 10
IS - 2
U1 - http://www.ncbi.nlm.nih.gov/pubmed/24586183?dopt=Abstract
ER -