Thyroid Hormone Levels and Your Genes

The thyroid is a master regulator that controls many of your body’s systems. It is integrally involved in metabolism and helps maintain body temperature, heart rate, breathing, and body weight.[ref]

Your genes play a big role in how well your thyroid works and how your body produces and converts the different forms of thyroid hormone.

This article explains how the thyroid works and which genetic variants impact thyroid function. It lists the specific thyroid-related variants you can check using your genetic raw data from 23andMe or AncestryDNA.

Thyroid Problems and Genetics

Thyroid hormone levels play a vital role in how you feel and in your overall health and wellbeing. A lot of people think of thyroid in terms of metabolism and weight, but your thyroid hormones also affect your body temperature, gut health, muscle energy, heart rate, skin health, bone health, and more.

Why is this important? In 2016, the #1 prescribed medication in the US was a thyroid medication (Synthroid), with 123 million people taking the drug.[ref]

Hypothyroidism, hyperthyroidism, and genetics:

Your body needs the right amount of thyroid hormones and at the right time. Hypothyroidism is caused by too little thyroid hormone; hyperthyroidism is caused by too much thyroid hormone.

If you have thyroid problems, learning which genetic variants you carry may be a way to shed some light on what is going on with your thyroid.

Knowing where your genetic susceptibilities lie can help you figure out (along with your doctor) the best way to solve the problem.

Symptoms of hypothyroidism include:

  • Fatigue
  • Feeling cold
  • Weight gain
  • Hair loss
  • Constipation
  • Shortness of Breath
  • Puffiness
  • Poor memory
  • Slow pulse
  • Lack of menstrual cycle

What produces thyroid hormones:

This system all starts in the brain instead of the thyroid. The hypothalamus, a region in the brain, and the pituitary gland control the thyroid gland’s rate of producing and releasing thyroid hormone.

  • The hypothalamus releases thyrotropin-releasing hormone (TRH), which signals to the pituitary gland.
  • The pituitary then creates and releases thyroid-stimulating hormone (TSH).

TSH then travels to the thyroid gland to signal for the production of thyroxine (T4) and triiodothyronine (T3).

T4, T3, and Iodine:

Iodine molecules are an essential part of the T4 and T3 hormones. There are specific transporters within the thyroid gland to move iodine (in the form of iodide) into the follicular cells where the T3 and T4 are produced. More on this in the genetics section below…

The balance of the two types of thyroid hormones (T4 and T3) is important.

  • T3 is the active form of the thyroid hormone that your body uses
  • T4 is the inactive form that can be converted into T3 when needed in your cells.

The thyroid gland produces and releases more T4 than T3  – around 80% is T4. Enzymes can convert T4 to T3 in your tissues and organs. Too much active T3 in cells will cause enzymes to inactivate the T3 into reverse T3 (rT3).[ref]

Thyroid hormone levels are an intricate balance between the production of T4, conversion to T3, inactivation to rT3, TSH levels, and the feedback loops controlling TRH and TSH.

What does the thyroid hormone do inside a cell?

Within cells, the thyroid hormone crosses into the nucleus and binds to a thyroid hormone receptor. These receptors then control the transcription of specific genes. Essentially, they turn on a gene so that whatever protein that gene codes for will get made.[ref]

In different cell types, the thyroid hormone receptors (THR) will control the production of different proteins.

  • For example, T3 can enter the cell nucleus and bind to the thyroid hormone receptor that controls the liver’s transcription (and production) of fatty acids (de novo lipogenesis).
  • Thyroid hormone receptors also regulate mitochondria production (the powerhouse of the cell) and the transcription of some genes within the mitochondria.[ref]

Going a little deeper: the thyroid hormone receptors in the cell nucleus don’t act alone. They are often bound with a retinoic acid receptor, which is activated by vitamin A. The thyroid hormone receptors also need zinc in the way that they bind to the DNA. It makes it important to have adequate vitamin A and zinc levels – along with producing enough thyroid hormone.[ref]

Finally, let me throw in that there are actually two different thyroid hormone receptors – THR-alpha and THR-beta. While both are located in most types of cells, THR-beta is the major form in the liver and THR-alpha is the major form in the heart cells and the bone.[ref]


Genes that impact thyroid hormone levels:

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Graphical overview of thyroid-related genes:

Thyroid Stimulating Hormone (TSH) related genes:

The basic thyroid test most doctors run is the TSH (thyroid-stimulating hormone) level.  Genetic variants in the TSH-related genes are responsible for approximately 50 – 90% of thyroid hormone variability.[ref] Thus, you can be naturally higher or lower on TSH levels due to genetic variants.

The TSHR gene (thyroid-stimulating hormone receptor) codes for a receptor protein that controls thyroid cell metabolism[ref]. TSH levels are tied to genetic variations of the TSHR gene.

Check your genetic data for rs1991517 D727E (23andMe v4; AncestryDNA):

  • C/C: typical
  • C/G: slightly lower TSH, increased risk of hypothyroidism and goiter
  • G/G: lower TSH, increased risk of hypothyroidism and goiter[ref][ref]

Members: Your genotype for rs1991517 is .

Check your genetic data for rs121908866 (23andMe v4;AncestryDNA);

  • A/A: congenital hypothyroidism
  • A/G: risk of congenital hypothyroidism[ref]
  • G/G: typical

Members: Your genotype for rs121908866 is .

Check your genetic data for rs121908867 (AncestryDNA);

  • C/T: risk of congenital hypothyroidism[ref]
  • C/C: typical

Members: Your genotype for rs121908867 is .

The PDE8B gene codes for a protein that causes the inactivation of cyclic AMP (important in energy regulation) in the thyroid. PDE8B genetic variants have been repeatedly associated with TSH levels, specifically in people of European background.[ref]

Check your genetic data for rs4704397 (23andMe v4, v5; AncestryDNA):

  • A/A: increase of approx. 0.26 – 0.29 uIU/ml in serum TSH[ref][ref]
  • A/G: increase of ~0.13 uIU/ml in serum TSH
  • G/G: typical

Members: Your genotype for rs4704397 is .

Check your genetic data for rs6885099 (23andMe v4, v5; AncestryDNA)

  • A/A: decreased TSH[ref]
  • A/G: slightly decreased TSH
  • G/G: typical

Members: Your genotype for rs6885099 is .

The FOXE1 gene (thyroid-specific forkhead transcription factor) has also been identified to increase the risk of primary hypothyroidism[ref] and changes in TSH levels.

Check your genetic data for rs7850258 (23andMe v4, v5; AncestryDNA):

  • A/A: Lower odds of hypothyroidism (OR = 0.74)[ref]
  • A/G: typical odds of hypothyroidism
  • G/G: typical (most common genotype)

Members: Your genotype for rs7850258 is .

Check your genetic data for rs965513 (23andMe v4, v5, AncestryDNA):

  • A/A: decreased TSH, increased risk of thyroid cancer[ref]
  • A/G: decreased TSH
  • G/G: typical

Members: Your genotype for rs965513 is .

 

DIO1, DIO2 – conversion of storage (T4) to active (T3):

DIO1 & DIO2 genes: The deiodinase 1 (DIO1) gene encodes a protein that converts T4 to T3 and is involved in the degradation of both T3 and T4 in the liver, kidney, thyroid, and pituitary gland. Iodine and selenium are involved in these reactions.[ref]  DIO2 is also involved in converting T4 to T3, mainly in the skeletal muscles, central nervous system, pituitary, thyroid, heart, and brown fat.[ref]

Check your genetic data for rs2235544 (23andMe v4, v5; AncestryDNA):

  • A/A: less active DIO1 – decreased free T3, a larger decrease in T3 due to organochloride pesticides[ref][ref]
  • A/C: intermediate (most common genotype in many populations)
  • C/C: more active DIO1enzyme – decreased free T4, increased fT3 (better ratio)[ref][ref]

Members: Your genotype for rs2235544 is .

Check your genetic data for rs11206244 (23andMe v4, v5; AncestryDNA):

  • T/T: higher rT3, lower free T3, higher fT4[ref][ref]
  • C/T: lower T3
  • C/C: typical

Members: Your genotype for rs11206244 is .

Check your genetic data for rs225014 (23andMe v4; AncestryDNA):

  • C/C: decreased DIO2 enzyme (T4 to T3 conversion)[ref] associated with improved wellbeing on combo T4 + T3 therapy vs. T4 alone[ref]
  • C/T: decreased  conversion of T4 to T3
  • T/T: typical; less likely to get Hashimoto’s or Graves'[ref]

Members: Your genotype for rs225014 is .

 

Autoimmune Thyroid – Graves’ and Hashimoto’s:

Graves’ disease is an autoimmune condition that affects about 1% of the population and causes hyperthyroidism. In Graves’ disease, the body produces antibodies against TSHR.

Hashimoto’s disease is an autoimmune condition that causes hypothyroidism. The prevalence of Hashimoto’s in Caucasian women is between 1-2%.[ref]

Genetic variants in the TSHR gene influence the risk of autoimmune thyroid diseases (AITD), including Graves’ disease and Hashimoto’s thyroiditis.  It is estimated that about 80% of the risk for autoimmune thyroid disease is due to genetics (with environmental factors making up the rest of the risk).[ref][ref]

Check your genetic data for rs3783938 (23andMe v4, AncestryDNA):

  • T/T: higher frequency of Hashimoto’s (OR 1.4)
  • C/T: higher frequency of Hashimoto’s
  • C/C: typical

Members: Your genotype for rs3783938 is .

Check your genetic data for rs12101255  (23andMe v4, AncestryDNA):

  • T/T: higher frequency of Graves’ disease (OR 1.4 – 1.8)[ref]  (very common genotype)
  • C/T: higher frequency of Graves’ disease
  • C/C: typical

Members: Your genotype for rs12101255 is .

Check your genetic results for rs179247 (23andMe v4, AncestryDNA):

  • A/A: increased risk of Graves’ disease (OR 1.4 – 1.8)[ref] (very common genotype)
  • A/G: typical
  • G/G: typical

Members: Your genotype for rs179247 is .

TPO Gene: Thyroid peroxidase (TPO) antibodies are a marker of autoimmune thyroid disease. Several genetic variants in the TPO gene are associated with an increased risk of autoimmune thyroid disease.

Check your genetic data for rs2071403 (23andMe v5; AncestryDNA.)

  • G/G: Most common genotype – increased risk of Graves and Hashimoto’s[ref]
  • A/G: no increased risk
  • A/A: no increased risk

Members: Your genotype for rs2071403 is .

The PTPN22 gene is associated with an increased risk of many autoimmune diseases, including Hashimoto’s.

Check your genetic data for rs2476601 (23andMe v4; AncestryDNA):

  • G/G: typical
  • A/G: slight increase in the risk of autoimmune thyroid disease
  • A/A: slight increase (OR 1.36)  in the risk of autoimmune thyroid disease[ref]

Members: Your genotype for rs2476601 is .

 

Rare causes of thyroid disease:

THRB & THRA genes: The thyroid hormone receptor genes code for the receptor that the thyroid hormone binds to in the cell’s nucleus. Mutations in these genes (rare!) cause thyroid hormone resistance.  Generally, THRB or THRA mutations will cause hypothyroidism that is recognized and diagnosed in infants or children.[ref] In other words, mutations cause more severe symptoms that affect growth and development.

Check your genetic data for rs28933408 (23andMe v4):

  • G/T: thyroid hormone resistance[ref]
  • G/G: typical

Members: Your genotype for rs28933408 is .

Check your genetic data for rs137853162 (AncestryDNA only)

  • G/T: thyroid hormone resistance[ref]
  • G/G: typical

Members: Your genotype for rs137853162 is .

SERPINA7 gene: codes for the thyroxine-binding globulin protein (On the X chromosome, so males have only one copy)

Check your genetic data for rs28933689 (23andMe v4 only):

  • A/T: Thyroxine-binding globulin deficiency[ref]
  • A/A: typical

Members: Your genotype for rs28933689 is .

Check your genetic data for rs2234036 (23andMe v4 only):

  • C/T: Thyroxine-binding globulin deficiency[ref]
  • C/C: typical

Members: Your genotype for rs2234036 is .

 


Lifehacks for thyroid problems:

If you are on thyroid medication or under a doctor’s care, please be sure to talk with your doctor about making any changes, including dietary changes, that could affect your thyroid hormone levels.

 What micronutrients and supplements help thyroid function?

  • Selenium is essential to the conversion of T4 to T3.  Brazil nuts are a good source of selenium, and supplements are also available.
  • Melatonin: The production of melatonin is regulated by TSH. Increasing melatonin increases thyroglobulin. The thyroid gland cells also synthesize melatonin.[ref] You can increase your melatonin levels naturally by blocking blue light at night or synthetically by taking melatonin at night.
  • Iodine: Make sure you get iodine in your diet through seafood, kelp, or iodized salt.
  • Myo-inositol: For autoimmune thyroid problems, Myo-inositol and selenium reduce antibody levels.[ref]
  • Vitamin D supplements reduce Hashimoto’s antibody levels.[ref]

Can changing diet and lifestyle improve thyroid function?

Gluten may be a problem for a few people:  Gluten is often pointed to as a culprit in autoimmune thyroid diseases (Graves and Hashimoto’s).  A 2003 study showed that ~5% of patients with autoimmune thyroiditis also had immune reactions to gluten.[ref]  While that isn’t a huge percentage, it may be worth trialing a gluten-free diet if you have an autoimmune thyroid disease. The flip side of that is also worth noting — 95% of people with autoimmune thyroid disease may have no problem with gluten.

Eat your fruits and veggies: The dietary flavonoid kaempferol, found in apples, onions, leeks, grapes, and other fruits and vegetables, induces DIO2, increasing conversion to T3.[ref]

Avoid fasting: In studies, fasting and critical illnesses increase the levels of DIO3, which is the enzyme that deactivates thyroid hormone.[ref] Fasting (and illness!) may be hard on your supply of active thyroid hormone.

Blocking blue lightLight and circadian rhythms play a role in DIO3 expression as well.[ref] Blocking blue light in the evening (from LED bulbs, TV screens, etc.) by wearing blue-blocking glasses will help to keep your circadian rhythm on track.

Blame mom: Several recent studies have also pointed to the hereditary epigenetic effects on DIO3 as well.[ref]

What toxicants affect thyroid function?

Studies on environmental toxins that impact thyroid function show:

  • PFAS (Perfluoroalkyl substances in cleaners, insecticides, flame retardants, carpet and fabric stain repellant, and food packaging) affect TSH levels[ref]
  • BPA and phthalates (in plastics and register receipts) affect thyroid levels.[ref] Read more about how genes play a role in your ability to detox BPA and phthalates.
  • Triclosan (previously used in antibacterial soaps) affects T3 and T4 levels as well as other markers.[ref]
  • Depending on your DIO2 genes, organochlorides (in pesticides) may make a significant difference in your thyroid levels.[ref]
  • Sucralose (Splenda) also alters thyroid hormone levels by increasing rT3 (a rat study)[ref]

 

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updated and revised 6/2020

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