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Genetics can affect our health in various ways. In some cases, we inherit propensities for particular health problems. We can also have changes to our genes that – along with lifestyle choices and the environment – contribute to developing specific health problems. To understand how genetics can affect thyroid function, you first need to understand the several vital systems that are in play:

• The hypothalamic-pituitary-thyroid (HPT) axis
• The thyroid hormone synthesis process
• The deiodination process

Your Guide To The Genetics Of Thyroid Function

Knowing your risk for thyroid disease can help you stay in front of complications. Learn in this guide how genes impact your risk for hypothyroidism.

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The hypothalamic-pituitary-thyroid (HPT) axis is a neuroendocrine system responsible for regulating metabolism and maintaining healthy circulating thyroid hormone levels. When the HPT axis is functioning:

• The hypothalamus senses low circulating levels of thyroid hormone and responds by releasing thyrotropin-releasing hormone (TRH). TRH is the master regulator of thyroid gland growth and function.
• TRH stimulates the pituitary gland to produce thyroid-stimulating hormone (TSH). TSH is a messenger hormone that communicates with the thyroid gland.
• TSH, in turn, stimulates the thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3).

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The production of thyroid hormone is initiated by the absorption of iodine from the GI tract. The iodine is reduced to iodide and released into the bloodstream3. The sodium iodide symporter transfers iodide to the thyroid follicular cells. The iodide is then oxidized into iodine by thyroid peroxidase (TPO). A chemical process with the amino acid tyrosine occurs, forming the thyroid hormones T4 and T3. The thyroid gland stores the T4 and T3 in thyroid follicles until they are released into the bloodstream.

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Deiodination is the process by which an iodine atom is removed from the T4 hormone and converted into T3. Deiodination is catalyzed by enzymes which are known as deiodinases. There are three types of deiodinases, and they act in a cell-specific manner to fine-tune thyroid hormone signaling.

• Type 1 and type 2 deiodinases convert T4 into T3
• Type 3 deiodinase inactivates T3 and T4 by converting T4 into reverse T3

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Let’s put it all together in a quick summary of the steps.

• First, at the big picture level, the hypothalamus monitors thyroid levels. When insufficient thyroid hormone is detected, it releases TRH to signal to the pituitary gland to produce and release TSH.
• TSH is then released to signal to the thyroid gland to release thyroid hormones. This feedback loop operates continuously.
• Meanwhile, iodine from the diet is being absorbed into the bloodstream.
• Sodium iodide symporters shuttle the iodide into thyroid follicular cells.
• There, thyroid peroxidase helps the iodine become oxidized.
• The oxidized iodine binds to thyroglobulin and, with the amino acid tyrosine, becomes T4 and T3 thyroid hormones.
• Deiodination of the T4 occurs with the aid of Type 1 and Type 2 deiodinase. During deiodination, the extra molecule is removed from the T4 hormone, and it’s converted into T3. (Sometimes, Type 3 deiodinase converts the T4 into reverse T3.)
• Thyroid hormones then bind to transport proteins and are transported into the bloodstream, where they go to cells.
• With the aid of thyroid transporters, thyroid hormones enter the cells. There, the hormones attach to the cell’s uptake receptors.

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The following graphic depicts an overview of the various processes.

We are still in the early stages of understanding how genetics can affect thyroid function. However, we already know that more than 100 different genes can affect thyroid function at various stages of the process, from the intake of iodine to the uptake of thyroid hormone in the cells. Gene polymorphisms –  changes in these genes – can create a genetic susceptibility to Hashimoto’s, hypothyroidism, and problems with T4-to-T3 conversion, among other issues. 

One of the most promising areas of study is evaluating the genetics of the deiodinases. Researcher and endocrinologist Antonio Bianco, MD, has led this effort. Dr. Bianco has identified genetic variations in DIO1, DIO2, and DIO3 – the DIO (deiodinase) genes – that affect deiodination. These genetic variations can impair the conversion of T4 into T3 or promote the conversion of T4 into inactive Reverse T3. Ultimately, impaired deiodination can lead to deficiencies of T3 and hypothyroidism at the cellular level and complicate the ability to treat hypothyroidism effectively.

Some of the other key genes involved in Hashimoto’s thyroiditis and hypothyroidism include:

• DUOX2 – involved in thyroid hormone production and synthesis
• The TSHB Gene – controls thyroid hormone synthesis
• TSHR and TRH Receptor Genes – affect thyroid hormone uptake at the cellular level
• FOXE1/TTF-2 (thyroid transcription factor 2) – associated with hypothyroidism
• PTPN22 (protein tyrosine phosphatase, non-receptor type 22) – associated with increased susceptibility to autoimmune thyroid disease and Hashimoto’s in particular
• HLA (human leukocyte antigen) class II region – associated with increased susceptibility to autoimmune thyroid disease and Hashimoto’s in particular
• CTLA-4 Gene (cytotoxic T lymphocyte antigen 4) – associated with increased susceptibility to autoimmune thyroid disease and Hashimoto’s in particular
• The Pendrin gene, also known as SLC26A4 – is involved in sodium/iodide symporter
• SLC5A5 – involved in the sodium/iodide transport process
• The TPO Gene – facilitates the oxidation of iodine
• THRA and THRB Genes – encode thyroid hormone receptors, control the release of thyroid hormone in response to TSH, and cause thyroid hormone resistance
• TSHR Gene – affects thyroid-stimulating hormone receptors
• The TRH Gene – is associated with TRH deficiency and central hypothyroidism, and complete thyroid resistance
• TG Gene – involved in the production of thyroglobulin, which is used for thyroid hormone production
• PROP1 and POU1F1 Genes – are associated with pituitary dysfunction and insufficient TSH production

Single nucleotide polymorphisms – abbreviated as SNPs and pronounced “snips” – are located on specific genes. These SNPs are associated with specific genetic variations that can be linked to particular thyroid-related issues. Some of the key SNPs related to thyroid function include:

• rs10917469 – associated with circulating TSH levels
• rs1991517 – associated with circulating TSH levels
• rs2071403 – associated with a predisposition to higher TPO antibodies and potential Hashimoto’s thyroiditis
• rs2235544 – associated with the free T3/free T4 ratio, and free T4 levels, conversion of T4 to T3, and rT3 levels
• rs2476601 – associated with autoimmunity and autoimmune thyroid disease
• rs2517532, rs2516049, associated with Epstein-Barr Virus and hypothyroidism
• rs3184504 – associated with hypothyroidism
• rs4704397 – associated with circulating TSH levels
• rs755109 – associated with TSH levels
• rs7850258 – related to the risk of primary hypothyroidism and elevated TSH levels
• rs925489  – associated with hypothyroidism
• rs965513  – related to the risk of autoimmune Hashimoto’s thyroiditis

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One of the simplest ways to evaluate your genes and SNPs for factors that affect your thyroid function is to get a 23 and Me Health and Ancestry panel. This panel identifies multiple genes and SNPs involved in thyroid function.

If you have questions about your results and how they affect your hypothyroidism diagnosis and treatment, we recommend you consult with one of Paloma’s top thyroid doctors for additional guidance.

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A quick summary: Your HPT axis, thyroid hormone synthesis, and deiodination all need to function normally and in a coordinated way for optimal thyroid function and stable hormone levels.

Genetic changes can affect – and interfere with – all the various steps in these processes. Specifically, genetic mutations and polymorphisms can:

• Impair your production of TRH, TSH, T4, and T3
• Affect your ability to respond to these hormones
• Interfere with the conversion of T4 into T3
• Impact the ability of your cells to receive and take up thyroid hormone

It’s clear that genetics can complicate your thyroid diagnosis and treatment. Thankfully, more research is underway to determine how best to integrate this information into hypothyroidism care.

But one thing is clear: going forward, it will become increasingly important to consider your genetic profile when diagnosing and treating Hashimoto’s thyroiditis and hypothyroidism.

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For more information, we recommend you read:

• How Your Genes Impact Your Risk Of Hypothyroidism‍
• You can also download a copy of the Paloma Guide to the Genetics of Thyroid Function

What is the hypothalamic-pituitary-thyroid (HPT) axis?

The HPT axis is the feedback system your body uses to regulate thyroid hormone levels. The hypothalamus senses low thyroid hormone and releases TRH, which signals the pituitary gland to produce TSH. TSH then signals the thyroid gland to release T4 and T3.

What is deiodination and why does it matter?

Deiodination is the process that converts T4 into active T3, carried out by enzymes called deiodinases. Genetic variations in the DIO1, DIO2, and DIO3 genes can impair this conversion, which can lead to T3 deficiency and make hypothyroidism harder to treat.

Can genetics affect my risk of Hashimoto's or hypothyroidism?

Yes. More than 100 genes have been linked to thyroid function, including genes involved in iodine uptake, thyroid hormone synthesis, and autoimmune susceptibility. Genetic variations, or polymorphisms, in these genes can increase your risk of developing Hashimoto's thyroiditis or hypothyroidism.

How can I test my genes for thyroid-related factors?

One option is a 23andMe Health and Ancestry panel, which can identify genes and SNPs involved in thyroid function. If your results raise questions about your hypothyroidism diagnosis or treatment, a thyroid doctor can help you interpret them.

What role do TSH, T4, and T3 play in thyroid function?

TSH is released by the pituitary gland to signal the thyroid to produce and release T4 and T3, the main thyroid hormones. T4 is then converted into the more active T3 through deiodination. This feedback loop operates continuously to keep hormone levels stable.