Thyroid Hormone Levels and Your Genes

The genes involved in hypothyroidism and Grave's.
The genes involved in hypothyroidism and hyperthyroidism.

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

Using your raw genetic data from 23andMe or another source, you can get an idea of areas that may be genetic weaknesses for you, possibly pointing to new approaches to managing your thyroid issues.

Why is this such a hot topic right now? More people than ever are having problems with low thyroid levels. In 2016, the #1 prescribed drug in the US was Synthroid, a synthetic thyroid hormone with 123 million people on the drug.[ref] Thyroid hormone levels play a vital role in how you feel and in your overall good health.

A quick overview (for those unfamiliar with thyroid):  thyroid hormones affect every cell in the body and control many functions such as metabolism, heart rate, body temperature, muscle contractions, and digestive functions.

The thyroid gland is located in the neck and uses iodine to create the thyroid hormones thyroxine(T4) and triiodothyronine(T3). The rate at which the thyroid gland produces and releases thyroid hormone is controlled by the hypothalamus and the pituitary gland through thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH).

Signs of Hypothyroidism (Wikimedia Commons)
Signs of Hypothyroidism (Wikimedia Commons)

Hypothyroidism is caused by too little thyroid hormone; hyperthyroidism is caused by too much thyroid hormone. T3 is the active form of thyroid.  The thyroid gland produces and releases much more T4 than T3 (around 90% more), but enzymes can convert T4 to T3 in your tissues and organs. Too much of the active T3 in cells will cause enzymes to inactivate it to reverse T3.

So you can see that thyroid hormone levels are an intricate balance between production of T4, conversion to T3, inactivation to rT3, TSH levels, and the feedback loops controlling TRH and TSH. So in addition to diet and environmental toxins, genetics can play a role at many points along the way.

A good source of background information on all things thyroid is the website (and book) Stop the Thyroid Madness.  If you are unfamiliar with the ins-and-outs of thyroid hormones, I recommend that you start there first.

T4 deiodinated to T3DIO1, DIO2T4 deactivated to rT3T3 converted to T2DIO3


Genetics  of thyroid hormone levels:
A person can be naturally slightly higher or lower than the average for TSH levels based on their genes.   An interesting study published in the journal of the European Society of Endocrinology looked at the heritability of thyroid hormone levels in men who had no thyroid auto-immune disease or dysfunction and found several SNPs that were responsible for approximately 50 – 90% of thyroid hormone variability.

TSHR – Thyroid stimulating hormone receptor (TSHR) gene codes for a receptor protein that controls thyroid cell metabolism. [ref]

TSH (thyroid stimulating hormone) levels are also tied to genetic variations. TSH levels are often the first thing that a doctor will check in regards to thyroid function, although some argue that TSH is not very useful in diagnosing hypothyroidism.

Check your 23andMe results for rs1991517 (v.4):

  • CC: normal
  • GG: slightly lower average TSH [ref]

Check your 23andMe results for rs179247 (v4):

  • AA: increased risk (slightly) of Grave’s [ref]
  • AG: increased risk (slight) of Grave’s
  • GG: normal risk of Grave’s

The PDE8B gene polymorphism is associated with TSH levels, specifically in those of European descent.[ref]  There are quite a few studies on this gene; a search in PubMed will give you more information.

Check your 23andMe results for rs4704397 (v.4, v.5):

  • AA: increase of 0.26 uIU/ml in serum TSH [ref]
  • AG: increase of 0.13 uIU/ml in serum TSH
  • GG: no increase in serum TSH

Check your 23andMe results for rs6885099 (v.4, v.5)

  • AA: increased serum TSH [ref]
  • AG: increased serum TSH
  • GG: normal serum TSH

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

Check your 23andMe results for rs7850258 (v.4, v.5):

  • AA: Lower odds of hypothyroidism (OR = 0.74)  [ref]
  • AG: Typical odds of hypothyroidism
  • GG: Slightly higher odds of hypothyroidism

Check your 23andMe results for rs965513 (v.4, v.5):

  • AA: decreased TSH, increased risk of thyroid cancer[ref]
  • AG: decreased TSH
  • GG: normal

AutoImmune Thyroid Gene Variants – Grave’s and Hashimoto’s

A 2012 study published in the Endocrine Journal showed that there are several SNPs in the TSHR gene that influence the risk of the autoimmune thyroid diseases (AITD), which includes Graves’ disease and Hashimoto’s thyroiditis.  The study states that “genetic factors confer 80% contribution to the etiology of AITD”.[ref]  Note that this does not mean that 80% of people with the SNPs have Graves’ or Hashimoto’s.  The prevalence of Hashimoto’s in Caucasian women is between 1 and 2% and is even less in men.[ref]

Check your 23andMe results for rs3783938 (v.4):

  • TT: higher frequency of Hashimoto’s (OR 1.4)
  • CT: higher frequency of Hashimoto’s
  • CC: normal

 

Check your 23andMe results for rs12101255 (v.4):

  • TT: higher frequency of Graves’ disease (OR 1.4 – 1.8) [ref]
  • CT: higher frequency of Graves’ disease
  • CC: normal

 

Check your 23andMe results for rs179247 (v.4):

  • AA: increased risk of Graves’ disease (OR 1.4 – 1.8) [ref]
  • GG: normal

 

DIO1, DIO2 – Deiodinase genes for conversion of storage (T4) to active (T3)

The deiodinase 1 (DIO1) gene encodes a protein that converts T4 to T3 and is involved in the degradation of both T3 and T4.  Iodine and selenium are involved in these reactions.  [ref]  DIO2 is also involved in the conversion of T4 to T3.

Check your 23andMe results for rs2235544 (v.4, v.5):

  • AA: decrease ratio of fT3 to fT4, decreased free T3  [ref]
  • CC: increased free T3 and decreased free T4

 

Check your 23andMe results for rs11206244 (v.4, v.5):

  • TT: higher rT3, lower free T3  [ref]
  • CT: lower T3
  • CC: normal

 

Check your 23andMe results for rs225014 (v.4):

  • CC: decreased DIO2 enzyme (T4 to T3 conversion)  [ref]
  • CT: decreased T4 to T3 conversion
  • TT: normal DIO2 enzyme

So why would these deiodinase polymorphisms be important?  The most common prescription for hypothyroidism is Synthroid, which is T4 only.  One reason for not doing well with Synthroid could be that the T4 is not being converted properly to T3 by the deiodinase enzymes.

Thyroid Hormone Receptors  (THRB, THRA)

Check your 23andMe results for rs28933408 (v.4): [snpedia]

  • TT: thyroid hormone resistance  [ref]
  • GG: normal

Lifehacks

  • Selenium is essential to the conversion of T4 to T3.  Brazil nuts are a good source of selenium, and supplements are also available.
  • The dietary flavonoid kaempferol, found in apples, onions, leeks, grapes, and other fruits and vegetables, induces DIO2 increasing conversion to T3. [study]
  • There are thyroid glandular supplements (dried thyroid gland) which may — or may not — increase thyroid hormones. The reviews are mixed. It is interesting to note that people historically ate most parts of animals including the thyroid gland.  Sweetbreads are the thyroid glands of calves or lambs.
  • 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.[study]  While that isn’t a huge percentage, it may be worth trialing a gluten-free diet if you have an autoimmune thyroid disease.
  • In studies, fasting and critical illnesses increase the levels of DIO3, which is the enzyme that deactivates thyroid hormone.[study]  Avoiding fasting (and illness!) should thus be better for thyroid hormone supply.
  • Light and circadian rhythms play a role in DIO3 expression as well.[study] 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.
  • Several recent studies have also pointed to the hereditary epigenetic effects on DIO3 as well.  [study]
  • For autoimmune thyroid problems, myo-inositol and selenium have been shown to reduce antibody levels. [study]
  • Vitamin D supplement has been shown to reduce Hashimoto’s antibody levels. [study]  This is the one that I use that has coconut oil instead of soybean oil.  (Not saying that anyone should by the brand because I use it — rather that you should make sure that read the ingredients so that you don’t end up with soybean oil or cottonseed oil.)

Recent studies on thyroid levels and chemical toxins:
With so many people having problems with thyroid hormone levels, the question becomes:  Why now? What is causing this explosion? The foods that we are eating and the fact that we no longer eat the thyroid glands of animals probably plays a role in the hypothyroid epidemic. Additionally, chemicals that are found in nearly everyone’s bloodstream, such as PFOA’s, BPA and phthalates, have been shown in several recent studies to be related to lower thyroid levels.  Study results include:

  • PFAS (Perfluoroalkyl substances in cleaners, insecticides, flame retardants, carpet and fabric stain repellant, and food packaging) affect TSH levels [study]
  • BPA and phthalates (in plastics and register receipts) affect thyroid levels.[study] 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. [study]
  • Depending on your DIO2 genes, organochlorides (in pesticides) may make a significant difference in your thyroid levels.[study]
  • Sucralose (Splenda) also alters thyroid hormone levels by increasing rT3 (a rat study) [study]

More to read
I encourage everyone who has thyroid problems to read and research more on this issue; you are your own best advocate. There is a lot more to learn about the topic:

Updated 4/2017

21 Replies to “Thyroid Hormone Levels and Your Genes”

  1. I was wondering if you ever considered changing the layout of your website?
    Its very well written; I love what youve got to say. But maybe you
    could a little more in the way of content so people could connect with it better.

    Youve got an awful lot of text for only having 1 or 2 pictures.
    Maybe you could space it out better?

  2. Love this info, but I think you have 1 or 2 typos in the SNPs’ I believe the deiodinase 1 (DIO1) gene’s SNP starts with “rs” no “rrs”. And the first SNP listed yielded a C/C for me, which should be an impossible base combo if the variants are all A and G.

  3. Hi

    This is a really useful website, so thanks for putting it together.
    I was particularly interested to see if I had a genetic issue causing ‘thyroid hormone resistance’, unfortunately my raw data did not include the SNP for this. In fact of the 11 different thyroid related SNP’s that you list my raw data contained only 5 of them.
    Can I just ask a few questions:
    1. Did 23andMe used to include all 11 SNP’s in the raw data, i.e. have they changed/reduced the amount of genetic info they now supply?
    2. Can I obtain info for the 6 SNP’s that weren’t included in my raw data from any other genetic testing source?
    3. My result for rs2235544 was AC, but you only gave the interpretation of AA and CC, do you know the significance of AC?

    Thanks for your help

    Mike

    1. Hi Mike –
      To answer your questions:
      1. Yes, everything listed on the page was on the version of the sequencing chip that 23andMe used up until mid-July-ish. I have it on my ‘to do’ list to take a look and update my blog posts to indicate whether the SNP is on the new chip or not. I’ll put the thyroid article on the top of the list since it is missing so many of the SNPs. My blog posts are only covering the variants on the older chip because that was the info that I had on myself… The new 23andMe data covers as many points as the old data (around 600,000 variants). I’ll dig back into the research when I update the page and see if there are other relevant SNPs that are now covered in the new 23andme data. I’ve had a couple of friends give me their new version of the data, so while it is different in places from the old, there may be all kinds of interesting things to find out from it :-)
      2. I don’t know if Ancestry or anyone else covers the snps that are listed in the article.
      3. Usually, the heterozygous form is somewhere in between the two homozygous forms, but not always. I’m only writing about what I find in the studies, which gave just the AA and CC for that SNP, so I didn’t want to go ahead and make the assumption and state that the AC form is something in between the two.
      Thanks for reading the blog! I’ll hopefully get the update done on the thyroid page within the next week or two.

      1. Hi

        Thanks for the reply and for answering my questions so fully. My 23andMe test was done in July/August, so I must have just missed the previous version of the sequencing chip, which is a real pity as the main reason I did the test was to find out if my suspicion that I have a defective gene for ‘thyroid hormone resistance’ was correct.
        Just my luck! But if you do find out if any other of the genetic testing companies include this particular SNP could you possibly let me know or put something up on your site – it would be really appreciated.
        I suppose ideally each company would include on their site a searchable data base, so that you could establish in advance of any test, if any specific SNP’s were included. Maybe in the future!

        Thanks for all your help

        Mike

  4. Here is something to consider when it comes to thyroid: one’s vitamin K status/how well one is making MK-4 appears to be very important.

    This is not known if this translates to humans, but in mice endogenously made MK-4 (menaquinone-4) is very high in thyroid.
    http://www.omicsgroup.com/conferences/ACS/conference/pdfs/9957-Speaker-Pdf-T.pdf
    [see slide 4]

    A recent publication further throws a wrench in the thinking about hypothyroidism for the last 4 decades:
    Is a Normal TSH Synonymous With “Euthyroidism” in Levothyroxine Monotherapy?
    https://academic.oup.com/jcem/article-abstract/101/12/4964/2765082?redirectedFrom=fulltext

    In the body of this publication, it is admitted that mice did NOT achieve euthroid status on T4 monotherapy in many tissues including brain, but that this had not been pursued in humans. (!) The corresponding author, a previous president of the American Thyroid Association, has discussed that the TSH may have issues and is questioning the standard of care for this condition for the last 4+ decades.

    Since mice had these issues when given T4 monotherapy, and since their thyroids are super high in MK-4, it would behoove us to look to see if this translates to humans.

    MK-4 is made from consumed vitamin K (both K1 and K2 of all forms) in a complex and recently discovered way. First, the K is converted in the small intestine to vitamin K3, menadione, which is then carried to distant tissues via the lymph system (not in the blood!) where it is then further converted into MK-4 which can then potentially bind SXR.

    All those blood measures miss this. Even the corresponding author of the questioning of dogma does not understand that the blood does not have K3 E-V-E-R, but that it is carried via lymph. Further, this conversion of K3 into the MK-4 form of vitamin K2 is done by the enzyme UBIAD1, which also controls calcium and cholesterol behavior in the cell. In fact, supplemental K2 in CKD patients lowered cholesterol, which went back up when supplementation was stopped.

    Vitamin K2 is mostly missing in diets and we have impaired vital vitamin K actions via such drugs as statins, bisphosphonates, warfaring and more. Look into it!
    Please see how this incredibly important nutrient/hormone has been vastly misunderstood! this is literally HUGE.

    1. Thanks so much for sharing all this! I’m going to have to dig into it more. The first thing that comes to mind is that our vitamin K status depends not only on diet and our microbiome, but there are quite a few genetic variants that alter our vitamin K status.
      Thanks again,
      Debbie

  5. I would be very interested in more info on Vit K and if there is a connection to thyroid as well as any SNPs to look for in Vit K.

    Also interested in Wilson’s Temperature Thyroid as well as what is called Low T3 Syndrome and how–and if–they are related to actual thyroid disorders.

    1. Hi,
      I’ve been digging into vitamin K metabolism for myself recently, but I haven’t gotten it put together into a blog post yet. One gene involved in vitamin K metabolism is VKORC1. There are quite a few studies on it (and other vitamin K genes) in relation to Warfarin metabolism. Snpedia.com would be a good place to start researching. I will probably get a blog post put together on it at some point…
      Here is one study that I have bookmarked on vitamin K and thyroid: https://www.ncbi.nlm.nih.gov/pubmed/21382270 I thought it was interesting that giving mice T3 suppressed vitamin K.
      And while I’ve read Dr. Wilson’s work on temperature syndrome, I haven’t been able to find a lot of studies that back it up. I wouldn’t say that there isn’t a scientific basis to it, and it probably works for some people. I suspect that it doesn’t work for everyone, probably due to genetic variations in the way people convert T3 to reverse T3.
      Debbie

  6. I have thyroid problems, but mine stem from exposure during Desert Storm; this is going to get sent straight to my VA endo, who blows me off routinely

    1. Hi Paul,
      You are the second person to mention Desert Storm to me this week. The first was a Patreon supporter who was wondering about the connections between genetics and Gulf War Illness. I looked up several studies for him, and there is a huge connection between certain genetic variants and the likelihood of effects from having taken pyridostigmine bromide.
      I’m working on an article now that explains all of that research, so please check back on this blog later this week. I’m not sure if there is specific research linking pyridostigmine bromide to thyroid disorders, but I know that bromide from other sources is linked to thyroid problems.
      Thank you for your service to our country,
      Debbie

      1. Perfect!! It wasn’t me, was it? I’m donating through Patreon too, and I’m pretty sure might’ve mentioned it to you. But hell, there’s 300,000 of us out there.

          1. A by product of military life. I go by my middle name, Paul, but the military goes by whatever name is first (Michael). It got easier to answer to either one than constantly correct everyone…

  7. Thank you so much for the great information.
    I found it frustrating that it would say “not genotyped” for many of these.

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