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Thyroid Genetics and the Cardiovascular System

  • Aleksander Kuś
  • Alexander Teumer
  • Layal Chaker
  • Marco MediciEmail author
Chapter
  • 39 Downloads

Abstract

Genetic factors are major determinants of thyroid function, and in the last two decades association studies have identified many genetic variants which are associated with thyroid-stimulating hormone (TSH) and thyroid hormone (TH) levels. In turn, thyroid function has been related to various cardiovascular diseases in observational studies. While both hypo- and hyperthyroidism have been associated with an increased risk of adverse cardiovascular outcomes, other studies showed that even minor variation in thyroid function within the normal range may affect the cardiovascular risk. In this chapter, we provide an overview of genetic factors involved in the regulation of thyroid function, and their relation with cardiovascular risk factors and outcomes. Moreover, we indicate how data from genetic association studies on thyroid function can be useful from a clinical perspective. Finally, we discuss current knowledge gaps and directions for future research.

Keywords

Thyroid TSH FT4 Heart Cardiovascular system Genetics Genome-wide association study 

References

  1. 1.
    Chaker L, et al. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: an individual participant data analysis. J Clin Endocrinol Metab. 2015;100(6):2181–91.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Moon S, et al. Subclinical hypothyroidism and the risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. Thyroid. 2018;28(9):1101–10.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Dekkers OM, et al. Acute cardiovascular events and all-cause mortality in patients with hyperthyroidism: a population-based cohort study. Eur J Endocrinol. 2017;176(1):1–9.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Collet TH, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012;172(10):799–809.CrossRefGoogle Scholar
  5. 5.
    Rodondi N, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365–74.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bano A, et al. Thyroid function and the risk of atherosclerotic cardiovascular morbidity and mortality: the Rotterdam Study. Circ Res. 2017;121(12):1392–400.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Chaker L, et al. Thyroid function within the reference range and the risk of stroke: an individual participant data analysis. J Clin Endocrinol Metab. 2016;101(11):4270–82.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Andersen S, et al. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87(3):1068–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Hansen PS, et al. Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. J Clin Endocrinol Metab. 2004;89(3):1181–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Teumer A, et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat Commun. 2018;9(1):4455.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Medici M, et al. Genetic determination of the hypothalamic-pituitary-thyroid axis: where do we stand? Endocr Rev. 2015;36(2):214–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Effraimidis G, Wiersinga WM. Mechanisms in endocrinology: autoimmune thyroid disease: old and new players. Eur J Endocrinol. 2014;170(6):R241–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Ploski R, Szymanski K, Bednarczuk T. The genetic basis of Graves’ disease. Curr Genomics. 2011;12(8):542–63.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hansen PS, et al. The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population. Clin Endocrinol. 2007;66(6):827–32.CrossRefGoogle Scholar
  15. 15.
    Peeters RP, et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab. 2003;88(6):2880–8.PubMedCrossRefGoogle Scholar
  16. 16.
    van der Deure WM, et al. Effects of serum TSH and FT4 levels and the TSHR-Asp727Glu polymorphism on bone: the Rotterdam Study. Clin Endocrinol. 2008;68(2):175–81.Google Scholar
  17. 17.
    Gabriel EM, et al. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endocrinol Metab. 1999;84(9):3328–35.PubMedGoogle Scholar
  18. 18.
    Nogueira CR, et al. Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas from Brazil. Thyroid. 1999;9(11):1063–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Sykiotis GP, et al. Functional significance of the thyrotropin receptor germline polymorphism D727E. Biochem Biophys Res Commun. 2003;301(4):1051–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Medici M, et al. A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur J Endocrinol. 2011;164(5):781–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Lago-Leston R, et al. Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of north-west Spain (Galicia). Clin Endocrinol. 2009;70(4):636–43.CrossRefGoogle Scholar
  22. 22.
    Roef GL, et al. Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones. Clin Chim Acta. 2013;425:227–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Ortiga-Carvalho TM, Sidhaye AR, Wondisford FE. Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol. 2014;10(10):582–91.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    van Gucht ALM, et al. Resistance to thyroid hormone due to heterozygous mutations in thyroid hormone receptor alpha. Curr Top Dev Biol. 2017;125:337–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Feng J, et al. Scanning of estrogen receptor alpha (ERalpha) and thyroid hormone receptor alpha (TRalpha) genes in patients with psychiatric diseases: four missense mutations identified in ERalpha gene. Am J Med Genet. 2001;105(4):369–74.PubMedCrossRefGoogle Scholar
  26. 26.
    Sorensen HG, et al. Identification and consequences of polymorphisms in the thyroid hormone receptor alpha and beta genes. Thyroid. 2008;18(10):1087–94.PubMedCrossRefGoogle Scholar
  27. 27.
    Arnaud-Lopez L, et al. Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. Am J Hum Genet. 2008;82(6):1270–80.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Gudmundsson J, et al. Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat Genet. 2012;44(3):319–22.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Porcu E, et al. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. 2013;9(2):e1003266.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Panicker V, et al. A locus on chromosome 1p36 is associated with thyrotropin and thyroid function as identified by genome-wide association study. Am J Hum Genet. 2010;87(3):430–5.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Rawal R, et al. Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function. Hum Mol Genet. 2012;21(14):3275–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Malinowski JR, et al. Genetic variants associated with serum thyroid stimulating hormone (TSH) levels in European Americans and African Americans from the eMERGE network. PLoS One. 2014;9(12):e111301.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Nielsen TR, et al. A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents. PLoS One. 2017;12(3):e0174204.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kwak SH, et al. A genome-wide association study on thyroid function and anti-thyroid peroxidase antibodies in Koreans. Hum Mol Genet. 2014;23(16):4433–42.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Zhan M, et al. Genome-wide association study identifies a novel susceptibility gene for serum TSH levels in Chinese populations. Hum Mol Genet. 2014;23(20):5505–17.PubMedCrossRefGoogle Scholar
  36. 36.
    Lowe JK, et al. Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae. PLoS Genet. 2009;5(2):e1000365.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Peeters RP, et al. A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans. J Clin Endocrinol Metab. 2005;90(1):256–63.PubMedCrossRefGoogle Scholar
  38. 38.
    de Jong FJ, et al. The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. J Clin Endocrinol Metab. 2007;92(2):636–40.PubMedCrossRefGoogle Scholar
  39. 39.
    Panicker V, et al. A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. J Clin Endocrinol Metab. 2008;93(8):3075–81.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Philibert RA, et al. The relationship of deiodinase 1 genotype and thyroid function to lifetime history of major depression in three independent populations. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(5):593–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Procopciuc LM, et al. The effect of the D1-C785T polymorphism in the type 1 iodothyronine deiodinase gene on the circulating thyroid hormone levels in Romanian women with preeclampsia. Association with the degree of severity and pregnancy outcome of preeclampsia. Gynecol Endocrinol. 2012;28(5):386–90.PubMedCrossRefGoogle Scholar
  42. 42.
    Roef G, et al. Heredity and lifestyle in the determination of between-subject variation in thyroid hormone levels in euthyroid men. Eur J Endocrinol. 2013;169(6):835–44.PubMedCrossRefGoogle Scholar
  43. 43.
    van der Deure WM, et al. The effect of genetic variation in the type 1 deiodinase gene on the interindividual variation in serum thyroid hormone levels: an investigation in healthy Danish twins. Clin Endocrinol. 2009;70(6):954–60.CrossRefGoogle Scholar
  44. 44.
    Peeters RP, et al. A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. Am J Physiol Endocrinol Metab. 2005;289(1):E75–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Coppotelli G, et al. Functional characterization of the 258 A/G (D2-ORFa-Gly3Asp) human type-2 deiodinase polymorphism: a naturally occurring variant increases the enzymatic activity by removing a putative repressor site in the 5' UTR of the gene. Thyroid. 2006;16(7):625–32.PubMedCrossRefGoogle Scholar
  46. 46.
    Pe’er I, et al. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol. 2008;32(4):381–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Taylor PN, et al. Whole-genome sequence-based analysis of thyroid function. Nat Commun. 2015;6:5681.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Gudbjartsson DF, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015;47(5):435–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Cangul H, et al. A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects. J Pediatr Endocrinol Metab. 2014;27(11–12):1101–5.PubMedGoogle Scholar
  50. 50.
    Marelli F, et al. In vivo functional consequences of human THRA variants expressed in the zebrafish. Thyroid. 2017;27(2):279–91.PubMedCrossRefGoogle Scholar
  51. 51.
    Dentice M, et al. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocrinol Metab. 2006;91(4):1428–33.PubMedCrossRefGoogle Scholar
  52. 52.
    Hermanns P, et al. Mutations in the NKX2.5 gene and the PAX8 promoter in a girl with thyroid dysgenesis. J Clin Endocrinol Metab. 2011;96(6):E977–81.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Narumi S, et al. Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients. J Clin Endocrinol Metab. 2010;95(4):1981–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Passeri E, et al. Increased risk for non-autoimmune hypothyroidism in young patients with congenital heart defects. J Clin Endocrinol Metab. 2011;96(7):E1115–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Razvi S, et al. Thyroid hormones and cardiovascular function and diseases. J Am Coll Cardiol. 2018;71(16):1781–96.CrossRefGoogle Scholar
  56. 56.
    Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med. 2004;164(15):1675–8.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Chaker L, et al. Normal thyroid function and the risk of atrial fibrillation: the Rotterdam Study. J Clin Endocrinol Metab. 2015;100(10):3718–24.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Baumgartner C, et al. Thyroid function within the normal range, subclinical hypothyroidism, and the risk of atrial fibrillation. Circulation. 2017;136(22):2100–16.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hebrant A, et al. Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations. Eur J Endocrinol. 2011;164(1):1–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Singh BK, Yen PM. A clinician’s guide to understanding resistance to thyroid hormone due to receptor mutations in the TRalpha and TRbeta isoforms. Clin Diabetes Endocrinol. 2017;3:8.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Clarke SL, Assimes TL. Genome-wide association studies of coronary artery disease: recent progress and challenges ahead. Curr Atheroscler Rep. 2018;20(9):47.PubMedCrossRefGoogle Scholar
  62. 62.
    Shu L, Blencowe M, Yang X. Translating GWAS findings to novel therapeutic targets for coronary artery disease. Front Cardiovasc Med. 2018;5:56.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Jorde R, et al. The phosphodiesterase 8B gene rs4704397 is associated with thyroid function, risk of myocardial infarction, and body height: the Tromso study. Thyroid. 2014;24(2):215–22.PubMedCrossRefGoogle Scholar
  64. 64.
    Medici M, Visser TJ, Peeters RP. Genetics of thyroid function. Best Pract Res Clin Endocrinol Metab. 2017;31(2):129–42.PubMedCrossRefGoogle Scholar
  65. 65.
    Torpy JM, Burke AE, Glass RM. JAMA patient page. Coronary heart disease risk factors. JAMA. 2009;302(21):2388.PubMedCrossRefGoogle Scholar
  66. 66.
    Ye Y, et al. Association between subclinical hypothyroidism and blood pressure—a meta-analysis of observational studies. Endocr Pract. 2014;20(2):150–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Prisant LM, Gujral JS, Mulloy AL. Hyperthyroidism: a secondary cause of isolated systolic hypertension. J Clin Hypertens (Greenwich). 2006;8(8):596–9.CrossRefGoogle Scholar
  68. 68.
    Asvold BO, et al. Association between blood pressure and serum thyroid-stimulating hormone concentration within the reference range: a population-based study. J Clin Endocrinol Metab. 2007;92(3):841–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Gumieniak O, et al. Ala92 type 2 deiodinase allele increases risk for the development of hypertension. Hypertension. 2007;49(3):461–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Maia AL, et al. Lack of association between the type 2 deiodinase A/G polymorphism and hypertensive traits: the Framingham Heart Study. Hypertension. 2008;51(4):e22–3.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Dora JM, et al. Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis. Eur J Endocrinol. 2010;163(3):427–34.PubMedCrossRefGoogle Scholar
  72. 72.
    van der Deure WM, et al. Impact of thyroid function and polymorphisms in the type 2 deiodinase on blood pressure: the Rotterdam Study and the Rotterdam Scan Study. Clin Endocrinol. 2009;71(1):137–44.CrossRefGoogle Scholar
  73. 73.
    Goumidi L, et al. Association between a thyroid hormone receptor-alpha gene polymorphism and blood pressure but not with coronary heart disease risk. Am J Hypertens. 2011;24(9):1027–34.PubMedCrossRefGoogle Scholar
  74. 74.
    Chaker L, et al. Thyroid function and risk of type 2 diabetes: a population-based prospective cohort study. BMC Med. 2016;14(1):150.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Peeters RP, et al. The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men. Clin Endocrinol. 2007;66(6):808–15.CrossRefGoogle Scholar
  76. 76.
    Mentuccia D, et al. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Diabetes. 2002;51(3):880–3.PubMedCrossRefGoogle Scholar
  77. 77.
    Mentuccia D, et al. The Thr92Ala deiodinase type 2 (DIO2) variant is not associated with type 2 diabetes or indices of insulin resistance in the old order of Amish. Thyroid. 2005;15(11):1223–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Maia AL, et al. The type 2 deiodinase (DIO2) A/G polymorphism is not associated with glycemic traits: the Framingham Heart Study. Thyroid. 2007;17(3):199–202.PubMedCrossRefGoogle Scholar
  79. 79.
    Grarup N, et al. Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 Danish white subjects. J Clin Endocrinol Metab. 2007;92(1):363–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Senee V, et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet. 2006;38(6):682–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Alexandrides T, Moses AC, Smith RJ. Developmental expression of receptors for insulin, insulin-like growth factor I (IGF-I), and IGF-II in rat skeletal muscle. Endocrinology. 1989;124(2):1064–76.PubMedCrossRefGoogle Scholar
  82. 82.
    Feldt-Rasmussen U. Interactions between growth hormone and the thyroid gland -- with special reference to biochemical diagnosis. Curr Med Chem. 2007;14(26):2783–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Laron Z. Interactions between the thyroid hormones and the hormones of the growth hormone axis. Pediatr Endocrinol Rev. 2003;1(Suppl 2):244–9; discussion 250.PubMedGoogle Scholar
  84. 84.
    Vincent AM, Feldman EL. Control of cell survival by IGF signaling pathways. Growth Hormon IGF Res. 2002;12(4):193–7.CrossRefGoogle Scholar
  85. 85.
    Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet. 2002;359(9302):248–52.PubMedCrossRefGoogle Scholar
  86. 86.
    Zheng J, et al. Recent developments in Mendelian randomization studies. Curr Epidemiol Rep. 2017;4(4):330–45.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Burgess S, et al. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology. 2017;28(1):30–42.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhao JV, Schooling CM. Thyroid function and ischemic heart disease: a Mendelian randomization study. Sci Rep. 2017;7(1):8515.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Consortium CAD, et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2013;45(1):25–33.CrossRefGoogle Scholar
  90. 90.
    Wilson PW, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837–47.PubMedCrossRefGoogle Scholar
  91. 91.
    Khera AV, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018;50(9):1219–24.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Khera AV, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375(24):2349–58.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Knowles JW, Ashley EA. Cardiovascular disease: the rise of the genetic risk score. PLoS Med. 2018;15(3):e1002546.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Panicker V, et al. Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab. 2009;94(5):1623–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Appelhof BC, et al. Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3′-triiodothyronine therapy. J Clin Endocrinol Metab. 2005;90(11):6296–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Medici M, et al. Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet. 2014;10(2):e1004123.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Schultheiss UT, et al. A genetic risk score for thyroid peroxidase antibodies associates with clinical thyroid disease in community-based populations. J Clin Endocrinol Metab. 2015;100(5):E799–807.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Chaker L, et al. Thyroid function characteristics and determinants: the Rotterdam Study. Thyroid. 2016;26(9):1195–204.PubMedCrossRefGoogle Scholar
  99. 99.
    Canaris GJ, et al. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160(4):526–34.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Wiersinga WM, et al. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1(2):55–71.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Manolio TA, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Aschard H, et al. Challenges and opportunities in genome-wide environmental interaction (GWEI) studies. Hum Genet. 2012;131(10):1591–613.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Ritchie MD, Van Steen K. The search for gene-gene interactions in genome-wide association studies: challenges in abundance of methods, practical considerations, and biological interpretation. Ann Transl Med. 2018;6(8):157.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Zuk O, et al. Searching for missing heritability: designing rare variant association studies. Proc Natl Acad Sci U S A. 2014;111(4):E455–64.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Parikh VN, Ashley EA. Next-generation sequencing in cardiovascular disease: present clinical applications and the horizon of precision medicine. Circulation. 2017;135(5):406–9.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Seidelmann SB, et al. Application of whole exome sequencing in the clinical diagnosis and management of inherited cardiovascular diseases in adults. Circ Cardiovasc Genet. 2017:10(1).Google Scholar
  107. 107.
    Khera AV, et al. Whole genome sequencing to characterize monogenic and polygenic contributions in patients hospitalized with early-onset myocardial infarction. Circulation. 2019;139:1593–602.PubMedCrossRefGoogle Scholar
  108. 108.
    Trerotola M, et al. Epigenetic inheritance and the missing heritability. Hum Genomics. 2015;9:17.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Fernandez-Sanles A, et al. Association between DNA methylation and coronary heart disease or other atherosclerotic events: a systematic review. Atherosclerosis. 2017;263:325–33.PubMedCrossRefGoogle Scholar
  110. 110.
    Pietzner M, Kacprowski T, Friedrich N. Empowering thyroid hormone research in human subjects using OMICs technologies. J Endocrinol. 2018;238(1):R13–29.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Aleksander Kuś
    • 1
    • 2
    • 3
  • Alexander Teumer
    • 4
    • 5
  • Layal Chaker
    • 1
    • 2
  • Marco Medici
    • 1
    • 2
    • 6
    Email author
  1. 1.Academic Center for Thyroid Diseases, Department of Internal MedicineErasmus Medical CenterRotterdamThe Netherlands
  2. 2.Department of EpidemiologyErasmus Medical CenterRotterdamThe Netherlands
  3. 3.Department of Internal Medicine and EndocrinologyMedical University of WarsawWarsawPoland
  4. 4.Institute for Community Medicine, University Medicine GreifswaldGreifswaldGermany
  5. 5.DZHK (German Center for Cardiovascular Research), partner site GreifswaldGreifswaldGermany
  6. 6.Division of Endocrinology, Department of Internal MedicineRadboud University Medical CenterNijmegenThe Netherlands

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