Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

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Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease


نویسنده	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.l.n. ,freathy r.m. ,shields b.m. ,pietzner d. ,nagy r. ,broer l. ,chaker l. ,korevaar t.i.m. ,plia m.g. ,sala c. ,völker 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. ,räikkönen 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. ,völzke h. ,cappola a. ,toniolo d. ,sanna s. ,naitza s. ,peeters r.p.
منبع	plos genetics - 2014 - دوره : 10 - شماره : 2
چکیده	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.

آدرس	department of internal medicine,erasmus medical center rotterdam,rotterdam, Netherlands, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari,italy,dipartimento di scienze biomediche,universita di sassari,sassari, Italy, division of genetics and cell biology,san raffaele scientific institute,milan, Italy, interfaculty institute for genetics and functional genomics,university medicine and ernst-moritz-arndt-university greifswald,greifswald, Germany, department of endocrinology and diabetes,sir charles gairdner hospital,nedlands,wa, Australia, cardiovascular health research unit,departments of medicine,epidemiology and health services,university of washington,seattle,wa, United States, institute for genetic epidemiology,helmholtz zentrum munich,munich/neuherberg, Germany, department of endocrinology and internal medicine,university hospital ghent,ghent university,ghent, Belgium, internal medicine,division of endocrinology,radboud university nijmegen medical center,nijmegen, Netherlands, department for health evidence,radboud university medical centre,nijmegen, Netherlands, institute of behavioural sciences,university of helsinki,helsinki, Finland, oxford centre for diabetes,endocrinology and metabolism and nihr oxford biomedical research centre,oxford,united kingdom,churchill hospital,headington,oxford, United Kingdom, research centre for prevention and health,glostrup university hospital,capital region of denmark,glostrup, Denmark, genetics of complex traits,university of exeter medical school,university of exeter,exeter, United Kingdom, peninsula nihr clinical research facility,university of exeter medical school,university of exeter,exeter, United Kingdom, institute of medical epidemiology,biostatistics,and informatics,martin-luther-university halle-wittenberg,halle, Germany, comprehensive cancer center,ohio state university,columbus,oh, United States, department of epidemiology,erasmus medical center rotterdam,rotterdam, Netherlands, department of internal medicine,erasmus medical center rotterdam,rotterdam, Netherlands, department of internal medicine,erasmus medical center rotterdam,rotterdam, Netherlands, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, division of genetics and cell biology,san raffaele scientific institute,milan, Italy, interfaculty institute for genetics and functional genomics,university medicine and ernst-moritz-arndt-university greifswald,greifswald, Germany, departments of medicine,human genetics,epidemiology and biostatistics,lady davis institute,mcgill university,montreal,canada,department of twin research and genetic epidemiology,king's college london,london, United Kingdom, department for health evidence,radboud university medical centre,nijmegen, Netherlands, institute for genetic epidemiology,helmholtz zentrum munich,munich/neuherberg, Germany, division of genetics and cell biology,san raffaele scientific institute,milan, Italy, national institute for health and welfare,helsinki,finland,hospital for children and adolescents,helsinki university central hospital,university of helsinki,helsinki, Finland, research centre for prevention and health,glostrup university hospital,capital region of denmark,glostrup, Denmark, department of endocrinology and internal medicine,university hospital ghent,ghent university,ghent, Belgium, department of internal medicine,erasmus medical center rotterdam,rotterdam, Netherlands, peninsula nihr clinical research facility,university of exeter medical school,university of exeter,exeter, United Kingdom, institute of laboratory medicine,clinical chemistry and molecular diagnostics,university hospital leipzig,leipzig, Germany, oxford centre for diabetes,endocrinology and metabolism and nihr oxford biomedical research centre,oxford, United Kingdom, comprehensive cancer center,ohio state university,columbus,oh, United States, interfaculty institute for genetics and functional genomics,university medicine and ernst-moritz-arndt-university greifswald,greifswald, Germany, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, dipartimento di scienze biomediche,universita di sassari,sassari, Italy, wellcome trust sanger institute,hixton, United Kingdom, division of genetics and cell biology,san raffaele scientific institute,milan, Italy, institute of clinical chemistry and laboratory medicine,university medicine greifswald,greifswald, Germany, institute of clinical chemistry and laboratory medicine,university medicine greifswald,greifswald, Germany, department for health evidence,radboud university medical centre,nijmegen, Netherlands, department of biostatistics,university of washington,seattle,wa, United States, oxford centre for diabetes,endocrinology and metabolism and nihr oxford biomedical research centre,oxford, United Kingdom, comprehensive cancer center,ohio state university,columbus,oh, United States, helmholtz zentrum muenchen,german research center for environmental health,institute of epidemiology ii,neuherberg, Germany, department of psychiatry and psychotherapy,university medicine greifswald,helios hospital stralsund,greifswald, Germany, division of genetics and cell biology,san raffaele scientific institute,milan, Italy, department for health evidence,radboud university medical centre,nijmegen, Netherlands, pathwest laboratory medicine wa,nedlands,wa, Australia, research unit of molecular epidemiology helmholtz zentrum münchen,german research center for environmental health,neuherberg, Germany, school of medicine and pharmacology,university of western australia,crawley,wa,australia,uwa centre for medical research,western australian institute for medical research,perth,wa, Australia, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, dipartimento di scienze biomediche,universita di sassari,sassari, Italy, school of population health,university of western australia,nedlands,wa, Australia, mrc lifecourse epidemiology unit,southampton general hospital,southampton, United Kingdom, pathwest laboratory medicine wa,nedlands,wa,australia,school of pathology and laboratory medicine,university of western australia,crawley,wa, Australia, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, high performance computing and network,crs4,parco tecnologico della sardegna,pula, Italy, center for statistical genetics,department of biostatistics,university of michigan,ann arbor,mi, United States, department of chronic disease prevention,national institute for health and welfare,helsinki,finland,vaasa health care centre,diabetes unit,vaasa, Finland, school of medicine and pharmacology,university of western australia,crawley,wa,australia,department of respiratory medicine,sir charles gairdner hospital,nedlands,wa, Australia, institute for molecular medicine finland (fimm),university of helsinki,helsinki, Finland, pathwest laboratory medicine wa,nedlands,wa, Australia, institute of human genetics,helmholtz zentrum munich,munich,germany,institute of human genetics,technische universität münchen,munich, Germany, department of cardiology and internal medicine,university hospital ghent,ghent university,ghent, Belgium, institute for molecular medicine finland (fimm),university of helsinki,helsinki,finland,wellcome trust sanger institute,wellcome trust genome campus,cambridge,united kingdom,department of medical genetics,university of helsinki and university central hospital,helsinki, Finland, diagnostica stago,doncaster,vic, Australia, pathwest laboratory medicine wa,nedlands,wa, Australia, institute of human genetics,helmholtz zentrum munich,munich, Germany, institute for translational genomics and population sciences,los angeles biomedical research institute,torrance,ca,united states,department of pediatrics,harbor-ucla medical center,torrance,ca, United States, institute of medical epidemiology,biostatistics,and informatics,martin-luther-university halle-wittenberg,halle, Germany, institute for community medicine,university medicine greifswald,greifswald, Germany, division of genetics and cell biology,san raffaele scientific institute,milan, Italy, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, comprehensive cancer center,ohio state university,columbus,oh, United States, school of clinical and experimental medicine,college of medical and dental sciences,univeristy of birmingham,edgbaston,birmingham, United Kingdom, institute of medical epidemiology,biostatistics,and informatics,martin-luther-university halle-wittenberg,halle, Germany, diabetes,endocrinology and vascular health centre,royal devon and exeter nhs foundation trust,exeter, United Kingdom, biobix lab. for bioinformatics and computational genomics,dept. of mathematical modelling,statistics and bioinformatics.,ghent university,ghent, Belgium, research centre for prevention and health,glostrup university hospital,capital region of denmark,glostrup,denmark,university of copenhagen,copenhagen, Denmark, national institute for health and welfare,helsinki,finland,department of general practice and primary health care,university of helsinki,helsinki,finland,helsinki university central hospital,unit of general practice,helsinki,finland,folkhalsan research centre,helsinki,finland,vasa central hospital,vasa, Finland, school of pathology and laboratory medicine,university of western australia,crawley,wa,australia,curtin health innovation research institute,curtin university of technology,bentley,wa, Australia, institute of epidemiology i,helmholtz zentrum munich,munich, Germany, internal medicine,division of endocrinology,radboud university nijmegen medical center,nijmegen, Netherlands, cardiovascular health research unit,departments of medicine,epidemiology and health services,university of washington,seattle,wa,united states,group health research institute,group health cooperative,seattle,wa, United States, institute for community medicine,university medicine greifswald,greifswald, Germany, department of epidemiology,erasmus medical center rotterdam,rotterdam, Netherlands, department of internal medicine,diabetes and endocrinology unit,san raffaele scientific institute,vita-salute san raffaele university,milan, Italy, laboratory of genetics,national institute on aging,baltimore,md, United States, institute of laboratory medicine,clinical chemistry and molecular diagnostics,university hospital leipzig,leipzig, Germany, institute for maternal and child health - irccs burlo garofolo,trieste,italy,university of trieste,trieste, Italy, department of epidemiology,erasmus medical center rotterdam,rotterdam, Netherlands, comprehensive cancer center,ohio state university,columbus,oh, United States, internal medicine,division of endocrinology,radboud university nijmegen medical center,nijmegen, Netherlands, oxford centre for diabetes,endocrinology and metabolism and nihr oxford biomedical research centre,oxford, United Kingdom, biopharmacy,department of pharmaceutical sciences,university basel,basel, Switzerland, genetics of complex traits,university of exeter medical school,university of exeter,exeter, United Kingdom, department of endocrinology and internal medicine,university hospital ghent,ghent university,ghent, Belgium, research centre for prevention and health,glostrup university hospital,capital region of denmark,glostrup, Denmark, institute of behavioural sciences,university of helsinki,helsinki, Finland, internal medicine,division of endocrinology,radboud university nijmegen medical center,nijmegen, Netherlands, department for health evidence,radboud university medical centre,nijmegen, Netherlands, department of internal medicine,erasmus medical center rotterdam,rotterdam,netherlands,department of epidemiology,erasmus medical center rotterdam,rotterdam,netherlands,netherlands consortium for healthy aging,netherlands genomics initiative,leiden, Netherlands, department of internal medicine,erasmus medical center rotterdam,rotterdam,netherlands,department of epidemiology,erasmus medical center rotterdam,rotterdam,netherlands,netherlands consortium for healthy aging,netherlands genomics initiative,leiden, Netherlands, department of endocrinology and diabetes,sir charles gairdner hospital,nedlands,wa,australia,school of medicine and pharmacology,university of western australia,crawley,wa, Australia, helmholtz zentrum muenchen,german research center for environmental health,institute of epidemiology ii,neuherberg, Germany, department of internal medicine,vu medical center,amsterdam, Netherlands, department of internal medicine,erasmus medical center rotterdam,rotterdam, Netherlands, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, department of endocrinology and diabetes,sir charles gairdner hospital,nedlands,wa,australia,school of medicine and pharmacology,university of western australia,crawley,wa,australia,department of twin research and genetic epidemiology,king's college london,london, United Kingdom, institute for community medicine,university medicine greifswald,greifswald, Germany, division of endocrinology,diabetes,and metabolism,perelman school of medicine at the university of pennsylvania,philadelphia,pa, United States, division of genetics and cell biology,san raffaele scientific institute,milan,italy,institute of molecular genetics-cnr,pavia, Italy, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, department of internal medicine,erasmus medical center rotterdam,rotterdam, Netherlands



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