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

English version České info

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.

Vyšlo v časopise: Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004123
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004123

Souhrn

Zdroje

1. GoughSC (2000) The genetics of Graves' disease. Endocrinol Metab Clin North Am 29 : 255–266.

2. SimmondsMJ, GoughSC (2004) Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA-4 and beyond. Clin Exp Immunol 136 : 1–10.

3. TunbridgeWM, EveredDC, HallR, AppletonD, BrewisM, et al. (1977) The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 7 : 481–493.

4. BiondiB (2012) Mechanisms in endocrinology: Heart failure and thyroid dysfunction. Eur J Endocrinol 167 : 609–618.

5. ColletTH, GusseklooJ, BauerDC, den ElzenWP, CappolaAR, et al. (2012) Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 172 : 799–809.

6. DavisJD, TremontG (2007) Neuropsychiatric aspects of hypothyroidism and treatment reversibility. Minerva Endocrinol 32 : 49–65.

7. GencerB, ColletTH, VirginiV, BauerDC, GusseklooJ, et al. (2012) Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation 126 : 1040–1049.

8. NichollsJJ, BrassillMJ, WilliamsGR, BassettJH (2012) The skeletal consequences of thyrotoxicosis. J Endocrinol 213 : 209–221.

9. RodondiN, den ElzenWP, BauerDC, CappolaAR, RazviS, et al. ((201)) Subclinical hypothyroidism and the risk of coronary heart disease and mortality. Jama 304 : 1365–1374.

10. RuhlaS, WeickertMO, ArafatAM, OsterhoffM, IskenF, et al. (2010) A high normal TSH is associated with the metabolic syndrome. Clin Endocrinol (Oxf) 72 : 696–701.

11. SelmerC, OlesenJB, HansenML, LindhardsenJ, OlsenAM, et al. (2012) The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study. Bmj 345: e7895.

12. PearceEN, FarwellAP, BravermanLE (2003) Thyroiditis. N Engl J Med 348 : 2646–2655.

13. SchweizerU, ChiuJ, KohrleJ (2008) Peroxides and peroxide-degrading enzymes in the thyroid. Antioxid Redox Signal 10 : 1577–1592.

14. BrixTH, HegedusL, GardasA, BangaJP, NielsenCH (2011) Monozygotic twin pairs discordant for Hashimoto's thyroiditis share a high proportion of thyroid peroxidase autoantibodies to the immunodominant region A. Further evidence for genetic transmission of epitopic “fingerprints”. Autoimmunity 44 : 188–194.

15. HuberG, StaubJJ, MeierC, MitracheC, GuglielmettiM, et al. (2002) Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab 87 : 3221–3226.

16. NielsenCH, BrixTH, LeslieRG, HegedusL (2009) A role for autoantibodies in enhancement of pro-inflammatory cytokine responses to a self-antigen, thyroid peroxidase. Clin Immunol 133 : 218–227.

17. StriederTG, PrummelMF, TijssenJG, EndertE, WiersingaWM (2003) Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease. Clin Endocrinol (Oxf) 59 : 396–401.

18. StriederTG, TijssenJG, WenzelBE, EndertE, WiersingaWM (2008) Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score. Arch Intern Med 168 : 1657–1663.

19. WeetmanAP (2000) Graves' disease. N Engl J Med 343 : 1236–1248.

20. BrixTH, HegedusL (2011) Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity. Ann Endocrinol (Paris) 72 : 103–107.

21. TomerY, DaviesTF (2003) Searching for the autoimmune thyroid disease susceptibility genes: from gene mapping to gene function. Endocr Rev 24 : 694–717.

22. KordonouriO, DeissD, DanneT, DorowA, BassirC, et al. (2002) Predictivity of thyroid autoantibodies for the development of thyroid disorders in children and adolescents with Type 1 diabetes. Diabet Med 19 : 518–521.

23. MediciM, de RijkeYB, PeetersRP, VisserW, de Muinck Keizer-SchramaSM, et al. (2012) Maternal early pregnancy and newborn thyroid hormone parameters: the Generation R study. J Clin Endocrinol Metab 97 : 646–652.

24. NegroR, MestmanJH (2011) Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab 25 : 927–943.

25. PoppeK, VelkeniersB, GlinoerD (2008) The role of thyroid autoimmunity in fertility and pregnancy. Nat Clin Pract Endocrinol Metab 4 : 394–405.

26. VanderpumpMP, TunbridgeWM, FrenchJM, AppletonD, BatesD, et al. (1995) The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 43 : 55–68.

27. HollowellJG, StaehlingNW, FlandersWD, HannonWH, GunterEW, et al. (2002) Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87 : 489–499.

28. WeetmanAP (2011) Diseases associated with thyroid autoimmunity: explanations for the expanding spectrum. Clin Endocrinol (Oxf) 74 : 411–418.

29. HansenPS, BrixTH, IachineI, KyvikKO, HegedusL (2006) The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins. Eur J Endocrinol 154 : 29–38.

30. LinnikMD, HuJZ, HeilbrunnKR, StrandV, HurleyFL, et al. (2005) Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus. Arthritis Rheum 52 : 1129–1137.

31. NielsenSF, BojesenSE, SchnohrP, NordestgaardBG (2012) Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. Bmj 345: e5244.

32. RaychaudhuriS, PlengeRM, RossinEJ, NgAC, PurcellSM, et al. (2009) Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet 5: e1000534.

33. RufJ, CarayonP (2006) Structural and functional aspects of thyroid peroxidase. Arch Biochem Biophys 445 : 269–277.

34. BakkerB, BikkerH, VulsmaT, de RandamieJS, WiedijkBM, et al. (2000) Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab 85 : 3708–3712.

35. BikkerH, BaasF, De VijlderJJ (1997) Molecular analysis of mutated thyroid peroxidase detected in patients with total iodide organification defects. J Clin Endocrinol Metab 82 : 649–653.

36. DennyJC, CrawfordDC, RitchieMD, BielinskiSJ, BasfordMA, et al. (2011) Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome -⁠ and phenome-wide studies. Am J Hum Genet 89 : 529–542.

37. ErikssonN, TungJY, KieferAK, HindsDA, FranckeU, et al. (2012) Novel associations for hypothyroidism include known autoimmune risk loci. PLoS One 7: e34442.

38. OrtizL, Aza-BlancP, ZanniniM, CatoAC, SantistebanP (1999) The interaction between the forkhead thyroid transcription factor TTF-2 and the constitutive factor CTF/NF-1 is required for efficient hormonal regulation of the thyroperoxidase gene transcription. J Biol Chem 274 : 15213–15221.

39. SimmondsMJ (2013) GWAS in autoimmune thyroid disease: redefining our understanding of pathogenesis. Nat Rev Endocrinol 9 : 277–287.

40. FaamB, DaneshpourMS, AziziF, SalehiM, HedayatiM (2012) Association between TPO gene polymorphisms and Anti-TPO level in Tehranian population: TLGS. Gene 498 : 116–119.

41. GudmundssonJ, SulemP, GudbjartssonDF, JonassonJG, MassonG, et al. (2012) Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat Genet 44 : 319–322.

42. PorcuE, MediciM, PistisG, VolpatoCB, WilsonSG, et al. (2013) A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet 9: e1003266.

43. WuY, DowbenkoD, SpencerS, LauraR, LeeJ, et al. (2000) Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J Biol Chem 275 : 21477–21485.

44. BossowskiA, CzarnockaB, BardadinK, Stasiak-BarmutaA, UrbanM, et al. (2008) Identification of apoptotic proteins in thyroid gland from patients with Graves' disease and Hashimoto's thyroiditis. Autoimmunity 41 : 163–173.

45. WangSH, BakerJR (2007) The role of apoptosis in thyroid autoimmunity. Thyroid 17 : 975–979.

46. BarrettJC, ClaytonDG, ConcannonP, AkolkarB, CooperJD, et al. (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41 : 703–707.

47. OrruV, TsaiSJ, RuedaB, FiorilloE, StanfordSM, et al. (2009) A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum Mol Genet 18 : 569–579.

48. RaychaudhuriS, RemmersEF, LeeAT, HackettR, GuiducciC, et al. (2008) Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 40 : 1216–1223.

49. VelagaMR, WilsonV, JenningsCE, OwenCJ, HeringtonS, et al. (2004) The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease. J Clin Endocrinol Metab 89 : 5862–5865.

50. SteerS, AbkevichV, GutinA, CordellHJ, GendallKL, et al. (2007) Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis. Genes Immun 8 : 57–68.

51. DuboisPC, TrynkaG, FrankeL, HuntKA, RomanosJ, et al. (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42 : 295–302.

52. FrankeA, McGovernDP, BarrettJC, WangK, Radford-SmithGL, et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42 : 1118–1125.

53. JinY, BirleaSA, FainPR, FerraraTM, BenS, et al. (2012) Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet 44 : 676–680.

54. SawcerS, HellenthalG, PirinenM, SpencerCC, PatsopoulosNA, et al. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476 : 214–219.

55. CooperJD, SimmondsMJ, WalkerNM, BurrenO, BrandOJ, et al. (2012) Seven newly identified loci for autoimmune thyroid disease. Hum Mol Genet 21 : 5202–5208.

56. MutoA, HoshinoH, MadisenL, YanaiN, ObinataM, et al. (1998) Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer. Embo J 17 : 5734–5743.

57. HouldenH, SingletonAB (2012) The genetics and neuropathology of Parkinson's disease. Acta Neuropathol 124 : 325–338.

58. LiuX, LuM, TangL, ZhangN, ChuiD, et al. (2013) ATXN2 CAG repeat expansions increase the risk for Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging 34 : 2236.e5–8.

59. MaganaJJ, Velazquez-PerezL, CisnerosB (2013) Spinocerebellar ataxia type 2: clinical presentation, molecular mechanisms, and therapeutic perspectives. Mol Neurobiol 47 : 90–104.

60. BonuccelliU, NutiA, MonzaniF, De NegriF, MuratorioA (1991) Familial occurrence of hypothyroidism and cerebellar ataxia. Funct Neurol 6 : 171–175.

61. TandeterH, LevyA, GutmanG, ShvartzmanP (2001) Subclinical thyroid disease in patients with Parkinson's disease. Arch Gerontol Geriatr 33 : 295–300.

62. KottgenA, AlbrechtE, TeumerA, VitartV, KrumsiekJ, et al. (2013) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 45 : 145–154.

63. KottgenA, PattaroC, BogerCA, FuchsbergerC, OldenM, et al. (2010) New loci associated with kidney function and chronic kidney disease. Nat Genet 42 : 376–384.

64. WainLV, VerwoertGC, O'ReillyPF, ShiG, JohnsonT, et al. (2011) Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet 43 : 1005–1011.

65. StahlEA, RaychaudhuriS, RemmersEF, XieG, EyreS, et al. (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42 : 508–514.

66. PlagnolV, HowsonJM, SmythDJ, WalkerN, HaflerJP, et al. (2011) Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases. PLoS Genet 7: e1002216.

67. GiegerC, RadhakrishnanA, CvejicA, TangW, PorcuE, et al. (2011) New gene functions in megakaryopoiesis and platelet formation. Nature 480 : 201–208.

68. KnausUG (2000) Rho GTPase signaling in inflammation and transformation. Immunol Res 21 : 103–109.

69. GramagliaI, WeinbergAD, LemonM, CroftM (1998) Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol 161 : 6510–6517.

70. ThangaratinamS, TanA, KnoxE, KilbyMD, FranklynJ, et al. (2011) Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. Bmj 342: d2616.

71. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 : 2190–2191.

72. MilaniG, MasciulloC, SalaC, BellazziR, BuettiI, et al. (2011) Computer-based genealogy reconstruction in founder populations. J Biomed Inform 44 : 997–1003.

73. PiliaG, ChenWM, ScuteriA, OrruM, AlbaiG, et al. (2006) Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2: e132.