Genetic Influence on Thyroid Stability

Many people suffer the effects of thyroid disease which include hypothyroidism, hyperthyroidism, Grave’s disease, Hashimoto’s thyroiditis (autoimmune thyroiditis), generalized thyroid inflammation and thyroid cancer.

Unrelated human subjects share 99.9% of their genome. It has been estimated that 90% of the remaining variation is accounted for by approximately 10 million common single nucleotide polymorphisms (SNPs), single base changes spread throughout the genome. These are very useful in studying gene-phenotype associations as they occur commonly in the general population, and may either cause changes in gene function themselves, or more frequently are markers of nearby elements that do.

Genetics play a prominent role in both determination of thyroid instability and increased disease risk. Heritability studies have suggested that up to 67% of circulating thyroid hormone and TSH concentrations are genetically determined, suggesting a genetic basis for narrow intra-individual variation in levels, perhaps a genetic ‘set point’.

Thyroid hormones play an essential role in normal human physiology with effects on almost all tissues to influence growth and development, maintain normal cognition, cardiovascular function, bone health, metabolism and energy balance. With increasing research in genetic implications we understand the important influence that genetics play in normal and abnormal thyroid function.  There is also strong connection in utilization and conversion of thyroid hormones in thyroid instability and there are certain genes that are involved in this conversion, for example, DIO1, DIO2, DIO3 are all involved.

Some genes known to influence thyroid function, including iodothyronine deiodinase 2 and the TSH receptor, have been shown to influence a wide range of clinical and developmental phenotypes from bone health to neurological development and longevity; such observations will help us understand the complex action of thyroid hormones on individual tissues.

Autoimmune thyroid disease commonly runs in families, and the search for genes that increase susceptibility has identified several good candidates, particularly those involved in immune regulation and thyroid function. However, these genes alone account for only a small percentage of the current prevalence of these disorders. Although the advancement of genetic technology has led to many significant findings in the last two decades, it is clear that we are only just beginning to understand the role of genetics in thyroid function and disease.[1][2][3][4][5][6][7][8][9]

There are many genes / variants that are integrally involved in thyroid function and regulation and key genes listed below are associated with thyroid functional changes.

Thyroid Top Gene List:

ABCD1, ADA, ADH7, AHCY, AIRE, AITD1, AITD2, AITD4, AKT1, AOX1, ATP5O, AVP, BAX, BGLAP, BMPR1A, C1QA, C1QB, C1QC, C1R, C1S, C2, C3, C4A, C4B, CALCA, CAPZB, CASP8, CBS, CCNA2, CCNB1, CCND3, CD163, CD1A, CD28, CD40, CD58, CD69, CD80, CDKN1B, CDKN2A, CDKN2B, CDKN3, CGA, CHKB, COL1A1, COMT, COQ2, COQ3, COX5A, COX6C, CRH, CRP, CSF1, CTLA4, CXCL8, CYP11A1, CYP17A1, CYP21A2, CYP27B1, DDC, DIO1, DIO2, DIO3, DUOX2, DUOXA2, EDN1, ENO1, FAS, FASLG, FCGR2B, FCRL2, FCRL3, FOXD3, FOXE1, FOXP3, GAD1, GAD2, GH1, GHR, GLIS3, GNAS, GPR174, GPX1, GPX3, GSTM1, GSTM3, GSTP1, HLA-A, HLA-B, HLA-DQA1, HLA-DQB1, HLA-DRB1, HLA-DRB4, HRAS, HSPD1, HT, ICAM1, ICAM3, IFIH1, IFNA1, IFNB1, IFNG, IFNG, IGF1, IGFBP1, IGFBP3, IGSF1, IL10, IL15, IL16, IL17A, IL18, IL1B, IL1R1, IL1RN, IL2, IL22, IL23R, IL2RA, IL2RB, IL4, IL5, IL6, IL7, IL7R, INS, ITPR3, IYD, LEP, LTA, MAOA, MAOB, MAP2K1, MBL2, MC2R, MET, MIF, MTHFR, NCOA4, NKX2-1, NKX2-5, NOS1, NOS2, NOS3, ODC1, PAX8, PDE8B, PICALM, PIK3CA, PLCG2, POMC, POU1F1, PRL, PROP1, PRSS3, PTEN, PTPN22, PTPRC, REN, RYR1, S100B, SCGB3A2, SECISBP2, SELENOS, SERPINA7, SERPING1, SHBG, SIRT1, SLC16A2, SLC1A4, SLC26A4, SLC30A8, SLC3A2, SLC5A5, SLCO1C1, SOD2, STAT3, TFAM, TG, TGFB1, THRA, THRB, TLR3, TMPO, TNF, TNFRSF11B, TNFSF13B, TP53, TP63, TPO, TRAF1, TRAP1, TRHR, TRPV1, TSHB, TSHR, TTR, VDR, VEGFA, ZFAT

 

Signs and Symptoms of Hypothyroidism

  • Fatigue
  • Increased sensitivity to cold
  • Constipation
  • Dry skin
  • Weight gain
  • Puffy face
  • Hoarseness
  • Muscle weakness
  • Elevated blood cholesterol level
  • Muscle aches, tenderness and stiffness
  • Pain, stiffness or swelling in your joints
  • Heavier than normal or irregular menstrual periods
  • Thinning hair
  • Slowed heart rate
  • Depression
  • Impaired memory
  • Anxiety

 

Signs and Symptoms of Hyperthyroidism

  • Sudden weight loss, even when your appetite and the amount and type of food you eat remain the same or even increase
  • Rapid heartbeat (tachycardia) — commonly more than 100 beats a minute — irregular heartbeat (arrhythmia) or pounding of your heart (palpitations)
  • Increased appetite
  • Nervousness, anxiety and irritability
  • Tremor — usually a fine trembling in your hands and fingers
  • Sweating
  • Changes in menstrual patterns
  • Increased sensitivity to heat
  • Changes in bowel patterns, especially more frequent bowel movements
  • An enlarged thyroid gland (goiter), which may appear as a swelling at the base of your neck
  • Fatigue, muscle weakness
  • Difficulty sleeping
  • Skin thinning
  • Fine, brittle hair

Signs and Symptoms of Grave’s Disease

  • Anxiety and irritability
  • A fine tremor of your hands or fingers
  • Heat sensitivity and an increase in perspiration or warm, moist skin
  • Weight loss, despite normal eating habits
  • Enlargement of your thyroid gland (goiter)
  • Change in menstrual cycles
  • Erectile dysfunction or reduced libido
  • Frequent bowel movements
  • Bulging eyes (Graves’ ophthalmopathy)
  • Fatigue
  • Thick, red skin usually on the shins or tops of the feet (Graves’ dermopathy)
  • Rapid or irregular heartbeat (palpitations)

 

Signs and Symptoms of Hashimoto’s Thyroiditis (Thyroid Autoinflammation)

  • Fatigue and sluggishness
  • Increased sensitivity to cold
  • Constipation
  • Pale, dry skin
  • A puffy face
  • Brittle nails
  • Hair loss
  • Enlargement of the tongue
  • Unexplained weight gain
  • Muscle aches, tenderness and stiffness
  • Joint pain and stiffness
  • Muscle weakness
  • Excessive or prolonged menstrual bleeding (menorrhagia)
  • Depression
  • Memory lapses

 

Signs and Symptoms of Thyroid Cancer

  • Neck pain:In many cases, neck pain starts in the front. In some cases the neck pain may extend all the way to the ears.
  • Voice changes:Experiencing hoarseness or other voice changes that do not go away could be a sign of thyroid cancer.
  • Breathing problems:Sometimes thyroid cancer patients say it feels like they are breathing through a straw. This breathing difficulty is often a symptom of the disease.
  • Coughing:A cough that continues and is not related to a cold.
  • Trouble swallowing:A growth or nodule on the thyroid gland may interfere with swallowing.

There are many genes  / variants implicated in thyroid cancer, but to name a few:

APC, CDC73, DICER1, MEN1, PRKAR1A, PTEN, RET, SDHB, SDHD, TP53, WRN

 

Conclusion

The ThyroidStabilityGS genetic panel curates gene relationships for hypothyroidism, hyperthyroidism, thyroid inflammation, Hashimoto’s thyroiditis, autoimmune thyroiditis and thyroid cancer risk for a more focused diagnosis and targeted treatable action plan.

 

Additional Resources:

  1. Thyroid Cancer Survivors
  2. Association Butterfly Thyroid Cancer Trust
  3. BHD Foundation
  4. National Parathyroid Education Foundation Pheo Para Troopers
  5. Association for Multiple Endocrine Neoplasia Disorders International Registry of Werner Syndrome
  6. NORD – Birt-Hogg-Dube Syndrome
  7. NORD – Carney Complex
  8. NORD – Familial Adenomatous Polyposis NORD – Pheochromocytoma
  9. NORD – Multiple Endocrine Neoplasia Type 2 NORD – Werner Syndrome
  10. Gene Reviews – Birt-Hogg-Dube Syndrome
  11. Gene Reviews – Carney Complex
  12. Gene Reviews – APC-Associated Polyposis Conditions
  13. Gene Reviews – Hereditary Paraganglioma-Pheochromocytoma Syndromes Gene Reviews – Li-Fraumeni Syndrome
  14. Gene Reviews – Multiple Endocrine Neoplasia Type 2
  15. Gene Reviews – Werner Syndrome

 

[1] Hansen PS, Brix TH, Sørensen TI, Kyvik KO, Hegedüs L. Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. J Clin Endocrinol Metab. 2004;89:1181–7.[PubMed]

 

[2] Samollow PB, Perez G, Kammerer CM, Finegold D, Zwartjes PW, Havill LM, et al. Genetic and environmental influences on thyroid hormone variation in Mexican Americans. J Clin Endocrinol Metab. 2004;89:3276–84.  [PubMed]

 

[3] Meikle AW, Stringham JD, Woodward MG, Nelson JC. Hereditary and environmental influences on the variation of thyroid hormones in normal male twins. J Clin Endocrinol Metab. 1988;66:588–92.  [PubMed]

 

[4] Andersen S, Pedersen KM, Bruun NH, Laurberg P. 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;87:1068–72.  [PubMed]

 

[5]  Panicker V, Wilson SG, Spector TD, Brown SJ, Falchi M, Richards JB, et al. Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol (Oxf) 2008;68:652–9.  [PubMed]

 

[6]  de Jong FJ, Peeters RP, den Heijer T, van der Deure WM, Hofman A, Uitterlinden AG, 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;92:636–40.  [PubMed]

 

[7] Panicker V, Saravanan P, Vaidya B, Evans J, Hattersley AT, Frayling TM, 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;94:1623–9.  [PubMed]

 

[8] van der Deure WM, Appelhof BC, Peeters RP, Wiersinga WM, Wekking EM, Huyser J, et al. Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients. Clin Endocrinol (Oxf) 2008;69:804–11.  [PubMed]

 

[9] Vaidya B, Kendall-Taylor P, Pearce SH. The genetics of autoimmune thyroid disease. J Clin Endocrinol Metab. 2002;87:5385–97.  [PubMed]