TTR gene: hereditary transthyretin amyloidosis

Once thought to be a rare genetic disease, new research shows that hereditary transthyretin amyloidosis (hATTR) may be more common, especially in people of African ancestry. The good news is that several new drugs are in clinical trials for hATTR. Understanding your genetic risk can help you seek treatment earlier before the damage is irreversible.

What does the TTR protein do?

The transthyretin (TTR) protein transports both thyroid hormone (T4, thyroxine) and retinol (a form of vitamin A) to the liver. The protein is named transthyretin because it transports thyroxine and retinol.

The TTR protein is made in the liver and in the choroid plexus, which is the region where cerebrospinal fluid is produced. It circulates through the bloodstream and the cerebrospinal fluid.

The thyroid secretes several different thyroid hormones. T4, or thyroxine, circulates bound to a protein — either bound to thyroid hormone-binding protein or bound to TTR.

Retinol, or vitamin A, is important in many biological functions, including regulating cell differentiation, neuron growth, and neuron survival. Retinol is transported in the bloodstream bound to retinol-binding protein and TTR. These two proteins together form a stable complex that keeps vitamin A from being broken down and excreted.[ref]

As you can see, the TTR protein has a couple of essential functions in the body.

Unfortunately, the TTR protein can also cause significant problems for a few people…

What is hATTR polyneuropathy?

Hereditary transthyretin amyloidosis (hATTR) is a genetic disease caused by mutations in the transthyretin (TTR) gene. These changes can impact the peripheral and autonomic nervous systems, as well as the cardiovascular system.

hATTR was formerly referred to as Transthyretin familial amyloid polyneuropathy (TTR-FAP) or transthyretin familial amyloid cardiomyopathy.

Extracellular deposition of the misfolded proteins (amyloids) causes hATTR symptoms.

The misfolded TTR proteins combine to form amyloid fibrils, causing cytotoxicity and tissue damage. The deposition of the amyloid fibrils in various tissues (nerve, heart, eyes, kidney, gastrointestinal mucosa) causes cellular damage and the subsequent symptoms of hATTR.

Quick terminology time-out: Amyloid is a general term applied to misfolded proteins that create a certain type of structural change. The overarching term for diseases caused by amyloids is amyloidosis. There are about three dozen different amyloidosis diseases, each due to a different protein that misfolds and causes fibrils to form. The most well-known is amyloid-beta (misfolded APP protein) which is implicated in causing Alzheimer’s disease.[ref]

TTR polyneuropathy symptoms often begin before age 50. Symptoms include:

  • paresthesia (pins and needles or numbness in the skin)
  • burning sensations or numbness, usually starting in the feet
  • dysautonomic nervous system problems (bowel issues, impotence,
  • dysesthesia (weird, unpleasant touch sensations, kind of like pain)

TTR cardiac symptoms can include cardiomyopathy and arrhythmia.[ref]

Other symptoms can include problems in the eyes, kidneys, carpal tunnel syndrome, and gastrointestinal issues.

hATTR possible symptoms. PMC7041433 CC image.

 

What causes hATTR?

Mutations in the TTR gene cause the hereditary form of TTR amyloidosis. Currently, over 120 known mutations in the gene are linked to hATTR. Some mutations are more likely to result in heart issues, while others usually present with nerve problems first.[ref]

Certain mutations are more commonly found in ancestry groups and locations:

  • rs76992529, or VI122I, is most common in African Americans and people of West African descent
  • rs28933979, or V30M, is most common in people of Portuguese, Northern Swedish, and Japanese descent
  • rs121918070, or T60A, is most common in people of Irish and British descent.
  • rs267607161, or A117S, is found in Chinese Malaysians.[ref]

In addition to the hereditary form of amyloid TTR, some people without mutations in the gene can also end up with proteins that misfold and aggregate. It is known as wild-type ATTR or wild-type transthyretin amyloid and mainly affects the heart. Wild-type ATTR is more likely in the elderly.


Genetic Mutations in the TTR gene:

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*Important: Please note that AncestryDNA data is not FDA approved for reporting on hATTR. 23andMe data is quality approved by the FDA on the first three mutations listed below. Keep in mind that these mutations below are just the most common ones. There are more than a hundred other really rare TTR mutations that 23andMe or AncestryDNA does not cover. Always get a second, clinical-grade test before making any major health-related decisions.

Check your genetic data for rs28933979 V30M (23andMe v4, v5 – i3002758)

  • G/G: typical
  • A/G: TTR mutation

Members: Your genotype for i3002758 is .

Check your genetic data for rs121918070 T60A (23andMe v4, v5 – i5004213)

  • A/A: typical
  • A/G: TTR mutation (found in up to 3% of African population groups)

Members: Your genotype for i5004213 is .

Check your genetic data for rs76992529 V122I (23andMe v4, v5 – also i3002759):

  • G/G: typical
  • A/G: TTR mutation, often cardiac related

Members: Your genotype for rs76992529 is .

Check your genetic data for rs267607161 A117S (AncestryDNA*)

  • G/G: typical
  • G/T: TTR mutation

Members: Your genotype for rs267607161 is .


Lifehacks:

If your genetic data shows a TTR mutation, talk with your doctor about testing to confirm.

Your doctor can also help with medications in clinical trials or recently approved for hATTR. You can read more about pharmaceutical treatments here: https://www.hattrguide.com/hattr-amyloidosis-treatment/

Supplement research for hATTR:

Several natural supplements may also interact with the TTR gene. The research on this is more theoretical than set in stone, but it is good to see that there may be ways to reduce the burden of amyloid TTR. For example:

  • Resveratrol has been shown to bind to the TTR protein.
  • Animal research shows that curcumin helps with the clearance of amyloid TTR. Curcumin binds to the thyroxine-binding site on TTR and may help prevent it from misfolding.[ref – full study]
  • EGCG, a component of green tea, shows that it may help clear amyloid TTR in cell studies.[ref]
  • A component of olive oil has some promise in research[ref]

Talk with your doctor about how supplements may help or interact with other medications.

Recap of your genetic variants:


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References:

Amyloidosis: Definition of Amyloid and Amyloidosis, Classification Systems, Systemic Amyloidoses. June 2022. eMedicine, https://emedicine.medscape.com/article/335414-overview.

Bemporad, Francesco, et al. “The Transthyretin/Oleuropein Aglycone Complex: A New Tool against TTR Amyloidosis.” Pharmaceuticals, vol. 15, no. 3, Feb. 2022, p. 277. PubMed Central, https://doi.org/10.3390/ph15030277.

Ferreira, Nelson, et al. “Curcumin: A Multi-Target Disease-Modifying Agent for Late-Stage Transthyretin Amyloidosis.” Scientific Reports, vol. 6, May 2016, p. 26623. PubMed Central, https://doi.org/10.1038/srep26623.

Liu, Yo‐Tsen, et al. “Biophysical Characterization and Modulation of Transthyretin Ala97Ser.” Annals of Clinical and Translational Neurology, vol. 6, no. 10, Sept. 2019, pp. 1961–70. PubMed Central, https://doi.org/10.1002/acn3.50887.

Low, Soon Chai, et al. “Ala97Ser Mutation Is Common among Ethnic Chinese Malaysians with Transthyretin Familial Amyloid Polyneuropathy.” Amyloid: The International Journal of Experimental and Clinical Investigation: The Official Journal of the International Society of Amyloidosis, vol. 26, no. sup1, 2019, pp. 7–8. PubMed, https://doi.org/10.1080/13506129.2019.1582479.

Luigetti, Marco, et al. “Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (HATTR) Polyneuropathy: Current Perspectives on Improving Patient Care.” Therapeutics and Clinical Risk Management, vol. 16, Feb. 2020, pp. 109–23. PubMed Central, https://doi.org/10.2147/TCRM.S219979.

Vieira, Marta, and Maria João Saraiva. “Transthyretin: A Multifaceted Protein.” BioMolecular Concepts, vol. 5, no. 1, Mar. 2014, pp. 45–54. www.degruyter.com, https://doi.org/10.1515/bmc-2013-0038.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.