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

2.50
Hdl Handle:
http://hdl.handle.net/11287/593875
Title:
Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease
Authors:
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.; Linneberg, A.; Raikkonen, K.; Smit, J. W.; Kiemeney, L. A.; Rivadeneira, F.; Uitterlinden, A. G.; Walsh, J. P.; Meisinger, C.; den Heijer, M.; Visser, T. J.; Simmonds, M. J.; Spector, T. D.; Wilson, S. G.; Volzke, H.; Cappola, A.; Toniolo, D.; Sanna, S.; Naitza, S.; Peeters, R. P.; Husemoen, L. L.; Freathy, Rachel M.; Shields, Beverley M; Pietzner, D.; Nagy, R.; Broer, L.; Chaker, L.; Korevaar, T. I.; 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, Andrew 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.; 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, Bijay; de Meyer, T.; Jorgensen, 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.; Meyer Zu Schwabedissen, H.; Frayling, Timothy M.; Kaufman, J. M.
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<5x10(-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 = 8.1x10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9x10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5x10(-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 = 1.2x10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2x10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9x10(-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.
Citation:
PLoS Genet. 2014 Feb;10(2):e1004123.
Publisher:
PloS
Journal:
PLoS genetics
Issue Date:
1-Feb-2014
URI:
http://hdl.handle.net/11287/593875
DOI:
10.1371/journal.pgen.1004123
PubMed ID:
24586183
Additional Links:
http://dx.plos.org/10.1371/journal.pgen.1004123
Note:
This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
Type:
Journal Article; Meta-Analysis; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1553-7404
Appears in Collections:
2014 RD&E publications; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMedici, M.en
dc.contributor.authorPorcu, E.en
dc.contributor.authorPistis, G.en
dc.contributor.authorTeumer, A.en
dc.contributor.authorBrown, S. J.en
dc.contributor.authorJensen, R. A.en
dc.contributor.authorRawal, R.en
dc.contributor.authorRoef, G. L.en
dc.contributor.authorPlantinga, T. S.en
dc.contributor.authorVermeulen, S. H.en
dc.contributor.authorLahti, J.en
dc.contributor.authorLinneberg, A.en
dc.contributor.authorRaikkonen, K.en
dc.contributor.authorSmit, J. W.en
dc.contributor.authorKiemeney, L. A.en
dc.contributor.authorRivadeneira, F.en
dc.contributor.authorUitterlinden, A. G.en
dc.contributor.authorWalsh, J. P.en
dc.contributor.authorMeisinger, C.en
dc.contributor.authorden Heijer, M.en
dc.contributor.authorVisser, T. J.en
dc.contributor.authorSimmonds, M. J.en
dc.contributor.authorSpector, T. D.en
dc.contributor.authorWilson, S. G.en
dc.contributor.authorVolzke, H.en
dc.contributor.authorCappola, A.en
dc.contributor.authorToniolo, D.en
dc.contributor.authorSanna, S.en
dc.contributor.authorNaitza, S.en
dc.contributor.authorPeeters, R. P.en
dc.contributor.authorHusemoen, L. L.en
dc.contributor.authorFreathy, Rachel M.en
dc.contributor.authorShields, Beverley Men
dc.contributor.authorPietzner, D.en
dc.contributor.authorNagy, R.en
dc.contributor.authorBroer, L.en
dc.contributor.authorChaker, L.en
dc.contributor.authorKorevaar, T. I.en
dc.contributor.authorPlia, M. G.en
dc.contributor.authorSala, C.en
dc.contributor.authorVolker, U.en
dc.contributor.authorRichards, J. B.en
dc.contributor.authorSweep, F. C.en
dc.contributor.authorGieger, C.en
dc.contributor.authorCorre, T.en
dc.contributor.authorKajantie, E.en
dc.contributor.authorThuesen, B.en
dc.contributor.authorTaes, Y. E.en
dc.contributor.authorVisser, W. E.en
dc.contributor.authorHattersley, Andrew T.en
dc.contributor.authorKratzsch, J.en
dc.contributor.authorHamilton, A.en
dc.contributor.authorLi, W.en
dc.contributor.authorHomuth, G.en
dc.contributor.authorLobina, M.en
dc.contributor.authorMariotti, S.en
dc.contributor.authorSoranzo, N.en
dc.contributor.authorCocca, M.en
dc.contributor.authorNauck, M.en
dc.contributor.authorSpielhagen, C.en
dc.contributor.authorRoss, A.en
dc.contributor.authorArnold, A.en
dc.contributor.authorvan de Bunt, M.en
dc.contributor.authorLiyanarachchi, S.en
dc.contributor.authorHeier, M.en
dc.contributor.authorGrabe, H. J.en
dc.contributor.authorMasciullo, C.en
dc.contributor.authorGalesloot, T. E.en
dc.contributor.authorLim, E. M.en
dc.contributor.authorReischl, E.en
dc.contributor.authorLeedman, P. J.en
dc.contributor.authorLai, S.en
dc.contributor.authorDelitala, A.en
dc.contributor.authorBremner, A. P.en
dc.contributor.authorPhilips, D. I.en
dc.contributor.authorBeilby, J. P.en
dc.contributor.authorMulas, A.en
dc.contributor.authorVocale, M.en
dc.contributor.authorAbecasis, G.en
dc.contributor.authorForsen, T.en
dc.contributor.authorJames, A.en
dc.contributor.authorWiden, E.en
dc.contributor.authorHui, J.en
dc.contributor.authorProkisch, H.en
dc.contributor.authorRietzschel, E. E.en
dc.contributor.authorPalotie, A.en
dc.contributor.authorFeddema, P.en
dc.contributor.authorFletcher, S. J.en
dc.contributor.authorSchramm, K.en
dc.contributor.authorRotter, J. I.en
dc.contributor.authorKluttig, A.en
dc.contributor.authorRadke, D.en
dc.contributor.authorTraglia, M.en
dc.contributor.authorSurdulescu, G. L.en
dc.contributor.authorHe, H.en
dc.contributor.authorFranklyn, J. A.en
dc.contributor.authorTiller, D.en
dc.contributor.authorVaidya, Bijayen
dc.contributor.authorde Meyer, T.en
dc.contributor.authorJorgensen, T.en
dc.contributor.authorEriksson, J. G.en
dc.contributor.authorO'Leary, P. C.en
dc.contributor.authorWichmann, E.en
dc.contributor.authorHermus, A. R.en
dc.contributor.authorPsaty, B. M.en
dc.contributor.authorIttermann, T.en
dc.contributor.authorHofman, A.en
dc.contributor.authorBosi, E.en
dc.contributor.authorSchlessinger, D.en
dc.contributor.authorWallaschofski, H.en
dc.contributor.authorPirastu, N.en
dc.contributor.authorAulchenko, Y. S.en
dc.contributor.authorde la Chapelle, A.en
dc.contributor.authorNetea-Maier, R. T.en
dc.contributor.authorGough, S. C.en
dc.contributor.authorMeyer Zu Schwabedissen, H.en
dc.contributor.authorFrayling, Timothy M.en
dc.contributor.authorKaufman, J. M.en
dc.date.accessioned2016-01-19T12:36:09Zen
dc.date.available2016-01-19T12:36:09Zen
dc.date.issued2014-02-01en
dc.identifier.citationPLoS Genet. 2014 Feb;10(2):e1004123.en
dc.identifier.issn1553-7404en
dc.identifier.pmid24586183en
dc.identifier.doi10.1371/journal.pgen.1004123en
dc.identifier.urihttp://hdl.handle.net/11287/593875en
dc.description.abstractAutoimmune 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<5x10(-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 = 8.1x10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9x10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5x10(-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 = 1.2x10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2x10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9x10(-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.en
dc.language.isoengen
dc.publisherPloSen
dc.relation.urlhttp://dx.plos.org/10.1371/journal.pgen.1004123en
dc.titleIdentification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid diseaseen
dc.typeJournal Articleen
dc.typeMeta-Analysisen
dc.typeResearch Support, N.I.H., Extramuralen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalPLoS geneticsen
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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