The DI01 mutation causes a change in the FT3/FT4 ratio

[diogenes]

This is a rather old post but will be interesting as regards the change in the FT3/FT4 ratio (ie conversion). The mutation allows more FT3 to be made from a given T4 dose.

J Clin Endocrinol Metab. 2008 Aug; 93(8): 3075–3081.

Published online 2008 May 20. doi: 10.1210/jc.2008-0397

PMCID: PMC2515080

PMID: 18492748

A Common Variation in Deiodinase 1 Gene DIO1 Is Associated with the Relative Levels of Free Thyroxine and Triiodothyronine

Vijay Panicker, Christie Cluett, Beverley Shields, Anna Murray, Kirstie S. Parnell, John R. B. Perry, Michael N. Weedon, Andrew Singleton, Dena Hernandez, Jonathan Evans, Claire Durant, Luigi Ferrucci, David Melzer, Ponnusamy Saravanan, Theo J. Visser, Graziano Ceresini, Andrew T. Hattersley, Bijay Vaidya, Colin M. Dayan, and Timothy M. Frayling

Excerpt:

The effect of rs2235544 on thyroid hormone levels is consistent with the C-allele being associated with higher deiodinase enzymatic activity (increased fT3/fT4 ratio and fT3 and decreased fT4 and rT3). This association is mainly driven by the strong association with decreased fT4 (see Table 3​3).). This association was present both in subjects on T4 replacement, with no endogenous T3 production, and those with normal thyroid function, suggesting that a significant amount of serum T3 is derived from peripheral deiodination of T4 in both populations.

[Nat107]

Thank you Diogenes x

[Musicmonkey]

Sorry, but what does this mean in layman's terms please? I have faulty gene DIO2 passed down from one parent. What does this excerpt mean to someone like me? Thank you diogenes

[diogenes Remembering in reply to Musicmonkey]

The same author wrote about DI02 mutations and their effects in 2009-full text links. This contrasts how the DI02 mutation can affect thyroid effects.

J Clin Endocrinol Metab. 2009 May;94(5):1623-9. doi: 10.1210/jc.2008-1301. Epub 2009 Feb 3.

Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients

Vijay Panicker 1 , Ponnusamy Saravanan, Bijay Vaidya, Jonathan Evans, Andrew T Hattersley, Timothy M Frayling, Colin M Dayan

PMID: 19190113 DOI: 10.1210/jc.2008-1301

Abstract

Introduction: Animal studies suggest that up to 80% of intracellular T(3) in the brain is derived from circulating T(4) by local deiodination. We hypothesized that in patients on T(4) common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T(4)/T(3) without necessarily affecting serum thyroid hormone levels.

Methods: We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T(4)/T(3) in 552 subjects on T(4) from the Weston Area T(4) T(3) Study (WATTS). Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12).

Results: The rarer CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2) was present in 16% of the study population and was associated with worse baseline GHQ scores in patients on T(4) (CC vs. TT genotype: 14.1 vs. 12.8, P = 0.03). In addition, this genotype showed greater improvement on T(4)/T(3) therapy compared with T(4) only by 2.3 GHQ points at 3 months and 1.4 at 12 months (P = 0.03 for repeated measures ANOVA). This polymorphism had no impact on circulating thyroid hormone levels.

Conclusions: Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T(4) and enhanced response to combination T(4)/T(3) therapy, but did not affect serum thyroid hormone levels.

[Musicmonkey]

Sorry I misread the genetic fault you were referring to, but, lucky me, I also have faulty gene DIO1, rs2235544 A (defective) and C (no defect) heterozygous.

I think I am very strange indeed, because when diagnosed in 2008, my TSH was 2.9, yet my T4 was below the 12-22 range at 10. I feel I have Central hypothyroidism, so my TSH is not within range, now that I am on 30mcg T3 and 25mcg T4 daily. This is concerning my Endo who is only guided by TSH and won't give me a small increase of T3 😥😥

[BB001]

At last, research talking about the Dio1 mutation! Most of what we hear seems to focus on DIO2 mutations (which I don't have).

DIO1 rs2235544 = AA [Red], (bad mutation = AA)

SNPedia says

'Risk of significantly decreased T4-T3 thyroid conversion, may worsen bone loss, brain effects'.

I also have

DIO1 rs11206244 = TC [Amber],

(bad mutation = CC)

SNPedia says

'Slight risk of decreased thyroid hormone metabolism'.

This can't be the whole picture though, as my T4 to T3 conversion rate when on levothyroxine is 0.16. In your research, Diogenes, this puts me in the range of a 'poor converter', though I think I warrant a new category of 'abysmal converter'!

[tattybogle in reply to BB001]

interesting paragraph explaining how DIO1 / DIO2 / DIO3 work:

joe.bioscientifica.com/view...

"It is known that deiodination contributes greatly to the conversion of T4 into the biologically active T3 through outer-ring deiodination and to the degradation of T4 and T3 to respectively reversed T3 (rT3) and the inactive TH metabolite 3,3’-diiodothyronine (T2) through inner ring deiodination.

Three types of deiodinases (DIO1, DIO2 and DIO3) are known and have distinct functions in the (in)activation of TH (van der Spek et al. 2017).

DIO1 is able to perform both inner- and outer-ring deiodination. Its main role is the degradation of inactivated TH; however, DIO1 also plays a role in the conversion of T4 into the biologically active T3, especially in the liver.

DIO2 has predominantly an activation role and is only capable of outer-ring deiodination and prefers deiodinating T4 into T3.

The function of DIO3 is to inactivate TH, since it is only capable of inner-ring deiodination, DIO3 catalyzes the conversion of T3 into T2 and T4 into rT3.

Interestingly, not all types are present in the same tissue. DIO1 is located in the liver, kidney, thyroid, and pituitary, whereas DIO2 is among others expressed in many brain areas, pituitary, brown adipose tissue, placenta, skeletal muscle, and macrophages. DIO3 is predominantly present in the placenta and neurons in the brain and plays a role in fetal development (Köhrle 2000).

Genetic variation in deiodinases is common (Taylor et al. 2015) and previous research in deiodinase knock-out mice proved aberrant serum TH concentrations compared to wild-type ( WT) mice. In general, deiodinases contribute largely to TH tissue status and defects are of interest for the regulation of TH concentrations in specific tissues."

(TH= 'Thyroid Hormones' )

[adin]

Very interesting but how can this be fixed. I am curious about what analysis I have to do to find out if I have these defective genes.

[diogenes Remembering in reply to adin]

If when well, your FT3/FT4 ratio was normal, it indicates adequate conversion. When on T4, at least for DI01 mutations you might have a more seemingly normal ratio because the gene is promoing more FT3 for the same FT4. For DI02 this doesn't seem to happen. If you have a DI01 or 02 mutation, with one gene normal and the other mutant then if the normal type is dominant you will see only a small difference from the normal state. It's mainly when the genes from both parents are mutant that the problems really show themselves.

[adin in reply to diogenes]

Thanks for the explanations. I wonder what are the assays for the two enzymes called?

[tattybogle in reply to adin]

Don't think they can test for these gene variants to DIo1/2 (or the enzymes themselves ) with assays .. tests looking for the variants are done by genetic /DNA testing

See replies by slowdragon at the end of this post for details of Dio2 testing healthunlocked.com/thyroidu...

[BB001 in reply to diogenes]

When on T4, at least for DI01 mutations you might have a more seemingly normal ratio because the gene is promoing more FT3 for the same FT4.

If I'm reading this correctly, this doesn't seem to be true for me. My fT3:fT4 ratio when on T4 was 0.16 (which is definitely not normal). I am homozygous for DIO1 rs2235544, and heterozygous for DIO1 rs11206244.

Have I misunderstood? Or is there something else going on?

[radd in reply to BB001]

BB001,

Your genetic results are only an indication of what might be contributory factors in the cause of your hypo and considered in the most probable terms. Even with more complex genetic testing the resulting behaviours can never be 100% conclusively known because of the sheer number of possibilities.

The chance of a genetic condition being passed on applies equally to each pregnancy but is so multifactorially dependant in both the passing on and how it should present were it to be passed on.

Therefore, depending upon the rest of our make-up a DIO1 mutation could actually be beneficial by up-regulating FT3 conversion. (That’s why is better not to call all mutations ‘impairments’. )

People are usually horror struck with deiodinase gene mutations because they alter conversion ratios but these gene dictated adjustments can be positive, negative or make little difference if they are offset by another, for example changes in mitochondrial DNA which is used in the cell T4-T3 conversion.

[BB001 in reply to radd]

Thank you for your reply. My concluding is that:This research suggests Dio1 mutation upregulates conversion of T4 to T3, yet my experience indicates this is completely wrong, as my fT3/FT4 ratio was extremely poor. Thus there must be another factor involved that negates this Dio1 genetic mutation, or causes it to have the opposite effect.

[radd in reply to BB001]

BB001,

Yes, it has been known for some years this DIO1 mutation up-regulates FT3 conversion. Positive for some, but not for all and exactly why we mustn't blame all difficulties on just one or two findings.

Unwanted genetic behaviours can also be encouraged to work more positively for us by switching on or disabling other genes, etc. This is why we always go back to basics of in the case of thyroid issues, adequate iron & optimised nutrients to allow best chance of managing genes disruptive behaviours.

[BB001 in reply to radd]

Ok thanks. My iron and vitamins are optimal. So that leaves me with the difficulty of having Dio1 mutations but not having the standard response, in fact it's the opposite. Not helpful to prove to medics you need T3.