Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Authors:
Prof Bijay Vaidya
Prof Bijay Vaidya
Royal Devon & Exeter Hospital and University of Exeter Medical School
Exeter | United Kingdom
Marco Medici Eleonora Porcu Giorgio Pistis Alexander Teumer Suzanne J Brown Richard A Jensen Rajesh Rawal Greet L Roef Theo S Plantinga Sita H Vermeulen Jari Lahti Matthew J Simmonds Lise Lotte N Husemoen Rachel M Freathy Beverley M Shields Diana Pietzner Rebecca Nagy Linda Broer Layal Chaker Tim I M Korevaar Maria Grazia Plia Cinzia Sala Uwe Völker J Brent Richards Fred C Sweep Christian Gieger Tanguy Corre Eero Kajantie Betina Thuesen Youri E Taes W Edward Visser Andrew T Hattersley Jürgen Kratzsch Alexander Hamilton Wei Li Georg Homuth Monia Lobina Stefano Mariotti Nicole Soranzo Massimiliano Cocca Matthias Nauck Christin Spielhagen Alec Ross Alice Arnold Martijn van de Bunt Sandya Liyanarachchi Margit Heier Hans Jörgen Grabe Corrado Masciullo Tessel E Galesloot Ee M Lim Eva Reischl Peter J Leedman Sandra Lai Alessandro Delitala Alexandra P Bremner David I W Philips John P Beilby Antonella Mulas Matteo Vocale Goncalo Abecasis Tom Forsen Alan James Elisabeth Widen Jennie Hui Holger Prokisch Ernst E Rietzschel Aarno Palotie Peter Feddema Stephen J Fletcher Katharina Schramm Jerome I Rotter Alexander Kluttig Dörte Radke Michela Traglia Gabriela L Surdulescu Huiling He Jayne A Franklyn Daniel Tiller Tim de Meyer Torben Jørgensen Johan G Eriksson Peter C O'Leary Eric Wichmann Ad R Hermus Bruce M Psaty Till Ittermann Albert Hofman Emanuele Bosi David Schlessinger Henri Wallaschofski Nicola Pirastu Yurii S Aulchenko Albert de la Chapelle Romana T Netea-Maier Stephen C L Gough Henriette Meyer Zu Schwabedissen Timothy M Frayling Jean-Marc Kaufman Allan Linneberg Katri Räikkönen Johannes W A Smit Lambertus A Kiemeney Fernando Rivadeneira André G Uitterlinden John P Walsh Christa Meisinger Martin den Heijer Theo J Visser Timothy D Spector Scott G Wilson Henry Völzke Anne Cappola Daniela Toniolo Serena Sanna Silvia Naitza Robin P Peeters

PLoS Genet 2014 Feb 27;10(2):e1004123. Epub 2014 Feb 27.

Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

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.

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http://repub.eur.nl/pub/65428/REPUB_65428_OA.pdf
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http://dx.plos.org/10.1371/journal.pgen.1004123
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937134PMC
February 2014
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