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DIO2 gene polymorphism (rs225014 and others)

Discussion in 'General ME/CFS Discussion' started by pattismith, Jun 12, 2017.

  1. pattismith

    pattismith Senior Member

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    CFS/ME shares several common points with hypothyroism (and also with Autism subgroup), such as impairment of mytochondrial efficacity and consecutive increased lactatemia when more energy is needed (both in the blood and in the brain)...

    I happened to learn that my mother (also concerned by CFS/ME) carries one copy of the C allele on the rs225014 gene. (mutation that can impair the efficacity of the DIO2)

    I have not tested my genome yet, but I wonder if some of you have this test done?

    About the DIO2 polymorphism on rs225014:

    "The protein encoded by this gene belongs to the iodothyronine deiodinase family. It catalyzes the conversion of prohormone thyroxine (3,5,3',5'-tetraiodothyronine, T4) to the bioactive thyroid hormone (3,5,3'-triiodothyronine, T3) by outer ring 5'-deiodination. This gene is widely expressed, including in thyroid, placenta, pituitary and brain. It is thought to be responsible for the 'local' production of T3, and thus important in influencing thyroid hormone action in these tissues."

    https://www.ncbi.nlm.nih.gov/gene/1734

    it may be important for us to know our genetic status on this gene, because we all try L Carnitine as a supplement, and is is known to interfere with thyroid function:

    "By experiments on cells (neurons, hepatocytes, and fibroblasts) that are targets for thyroid hormones and a randomized clinical trial on iatrogenic hyperthyroidism, we validated the concept that L-carnitine is a peripheral antagonist of thyroid hormone action. In particular, L-carnitine inhibits both triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei."

    https://www.ncbi.nlm.nih.gov/pubmed/15591013

    I also have TPO antibodies, so I wonder if Carnitine is really acurate for me...
    TPO antibodies are very common antibodies, I wonder if they are more or less frequent in our CFS/ME community?
     
  2. Valentijn

    Valentijn The Diabolic Logic

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    That allele is extremely common - approximately 70% of people have one or two copies of it. It's not causing any disease.
     
  3. pattismith

    pattismith Senior Member

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    Well, DIO2 activity is difficult to mesure (no change in blood thyroid test associated with polymorphism on this gene) , because it is locally active (in the brain cells especially), but there are evidences that need to be duplicated in the studies among the hypothyroid patients showing that the carriers for polymorphism suffer from a lower DIO2 activity, so this mean that studies should investigate this gene further.

    "D2 catalyses the conversion of T4 into T3, and is especially important in the local control of thyroid hormone signalling [63]. Animal studies suggest that up to 80% of intracellular T3 in the brain is derived from circulating T4 by local deiodination into T3 via D2. Thus, D2 polymorphisms may affect T3 content in the brain without evident changes in circulating thyroid hormones. Two SNPs in DIO2 including Thr92Ala were not associated with well-being, neurocognitive functioning, and preference for combined L-T4 + L-T3 therapy [64]. These negative results are possibly due to the still limited sample size of 141 patients in this study, because a larger study among 552 patients on L-T4 replacement reported positive results [59]. The rarer phenotype rs225014 of DIO2 was present in 16% of the subjects on L-T4 therapy, and associated with worse scores on the General Health
    The results require replication but suggest that DIO2 polymorphisms are associated with impaired psychological well-being in patients on L-T4 replacement and enhanced response to L-T4 + L-T3 combination therapy."
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821467/

    In non hypothyroid patients

    Another haplotype of DIO2 was shown to be very important for the brain function, especially in an environment lacking Iodine:

    "Single marker analysis showed a positive association of children Mental Retardation with
    rs225012 and rs225010 Particularly with rs225012, TT genotype frequency was significantly higher in MR cases than in controls (x2=9.18, p=0.00246). When we compared the distributions of common haplotypes, we also found
    significant differences between mental retardation and controls in the haplotype combination of rs225012
    and rs225010. This association remained significant after Bonferroni correction (p=0.0016470).
    Conclusion:
    We conclude that allelic variation in the DIO2 gene may affect the amount of T3 available and
    in an iodine-deficient environment may partly determine overall risk of Mental Retardation."
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735866/pdf/v041p00585.pdf

    DIO are Selenoproteins, so we can suppose that DIO2 polymorphism with reduced activity may be more sensitive to selenium deficiency too!
     
  4. alicec

    alicec Senior Member

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    Australia
    Why do you think the common C allele (ie the ancestral or unchanged variant) of this SNP is of significance?

    The first reference (ie the first one in your first post) you cite is not about this SNP but about the DIO2 gene in general.

    In your second post one of the references does discuss this SNP but identifies the TT variant (ie the rarer altered variant) as being associated with worse psychological well being scores and better response to T4/T3 therapy compared with T4 alone.

    The other reference is about association of different SNPs with mental retardation in children in conditions of iodine deficiency.

    This does suggest that some polymorphisms in the gene may have some consequence (not a startling conclusion) but it's a stretch to think that this might somehow be relevant of ME/CFS.
     
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  5. pattismith

    pattismith Senior Member

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    sorry to be so confused alicec, my brain is not at its best.
    Yes my mother is C/T for the DIO2 exon rs225014, this is why I started to get interest in the DIO2 function.
    My grand mother was ill, my mother and I, so I have my reasons to focus on the genetic background of our disease.
    The T allele is not rare but it may impact on the local efficacity of the DIO2 in the brain (to convert locally T4 to T3) under some circunstances. Polymorphism on the two other exons might also impact the DIO2 local activity.
    I tryed to put links to the publications that show evidences of the impact the DIO2 polymorphisms can have under some circumstances.

    In normal people, these variants might not be harmful, but in certain conditions (general hypothyroidism, or lack of iodine and or selenium in the food), the brain may lack of T3, even if the blood thyroid tests are normal, which can lead to fatigue, depression, and more lactates in the brain.
    I know that CFS not only impact the brain but many other body areas (I had time to observe that for my 35 years of illness), but a lack of brain T3 would be very harmful in our case, more harmful than in normal people, so we have to take attention to it.
    I don't mean to accuse the less efficient DIO2 for the CFS/ME, I just say that it could make it worse.
    I hope I made it clearer, sorry if you think that my concern for the DIO2 activity was completly out of the subject.
    This will be my last post on this thread.
     

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