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

Medici, M., Porcu, E., Pistis, G., Teumer, A., Brown, S. J., Jensen, R. A., Rawal, R., Roef, G. L., Plantinga, T. S., Vermeulen, S. H., Lahti, J., Simmonds, M. J., Husemoen, L. N. N., Freathy, R. M., Shields, B. M., Pietzner, D., Nagy, R., Broer, L., Chaker, L., Korevaar, T. I. M., Plia, M. G., Sala, C., Volker, U., Richards, J. B., Sweep, F. C., Gieger, C., Corre, T., Kajantie, E., Thuesen, B., Taes, Y. E., Visser, W. E., Hattersley, A. T., Kratzsch, J., Hamilton, A., Li, W., Homuth, G., Lobina, M., Mariotti, S., Soranzo, N., Cocca, M., Nauck, M., Spielhagen, C., Ross, A., Arnold, A., van de Bunt, M., Liyanarachchi, S., Heier, M., Grabe, H. J., Masciullo, C., Galesloot, T. E., Lim, E. M., Reischl, E., Leedman, P. J., Lai, S., Delitala, A., Bremner, A. P., Philips, D. I. W., Beilby, J. P., Mulas, A., Vocale, M., Abecasis, G., Forsen, T., James, A., Widen, E., Hui, J., Prokisch, H., Rietzschel, E. E., Palotie, A., Feddema, P., Fletcher, S. J., Schramm, K., Rotter, J. I., Kluttig, A., Radke, D., Traglia, M., Surdulescu, G. L., He, H., Franklyn, J. A., Tiller, D., Vaidya, B., de Meyer, T., Jørgensen, T., Eriksson, J. G., O’Leary, P. C., Wichmann, E., Hermus, A. R., Psaty, B. M., Ittermann, T., Hofman, A., Bosi, E., Schlessinger, D., Wallaschofski, H., Pirastu, N., Aulchenko, Y.S., de la Chapelle, A., Netea-Maier, R.T., Gough, S.C.L., Meyer zu Schwabedissen, H., Frayling, T.M., Kaufman, J.M., Linneberg, A., Raikkonen, K., Smit, J.W.A., Kiemeney, L.A., Rivadeneira, F., Uitterlinden, A.G., Walsh, J.P., Meisinger, C., den Heijer, M., Visser, T.J., Spector, T.D., Wilson, S.G., Volzke, H., Cappola, A., Toniolo, D., Sanna, S., Naitza, S. and Peeters, R.P. (2014) Identification of novel genetic loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genetics, 10 (2). ISSN 1553-7390

Full content URL: http://dx.doi.org/10.1371/journal.pgen.1004123

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Abstract

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. © 2014.

Keywords:thyroid peroxidase antibody, thyrotropin, autoantibody, iodide peroxidase, thyroid microsomal antibodies, thyrotropin, adult, aged, antibody blood level, article, ATXN2 gene, autoimmune disease, autoimmune thyroid disease, autoimmunity, Bach2 gene, cancer risk, controlled study, female, gene, gene frequency, gene identification, gene locus, genetic association, genetic variability, goiter, Graves disease, Hashimoto disease, human, kalrn gene, MAGI3 gene, major clinical study, male, risk assessment, risk factor, risk reduction, scoring system, single nucleotide polymorphism, subclinical hyperthyroidism, subclinical hypothyroidism, thyroid cancer, thyroid disease, TPO gene, genetics, immunology, isolation and purification, meta analysis, metabolism, pathology, Autoantibodies, Genetic Loci, Genome-Wide Association Study, Humans, Risk Factors, NotOAChecked
Subjects:C Biological Sciences > C420 Human Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:22594
Deposited On:16 Mar 2016 15:06

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