REVIEW: DIO1 gene affects T3:T4 ratio

Panicker et al, 2008

Click title to read it online: A Common Variation in Deiodinase 1 Gene DIO1 Is Associated with the Relative Levels of Free Thyroxine and Triiodothyronine

Background

• “D1 is found in liver, kidney, thyroid, and pituitary” and as blood flows through these organs, D1 converts T4 into T3, increasing levels of Free T3 in serum (bloodstream)
• In contrast, we see “D2 in skeletal muscle, central nervous system, pituitary, thyroid, heart, and brown adipose tissue” where T4 gets converted to T3 locally, inside of cells and tissues.

Main findings of the study

• The study found “a common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T₃ to free T₄.”
• This  was significant in patients on L-T4 therapy as well as patients not on therapy.
• “There was no effect on serum TSH levels.”

What were the T3:T4 ratios?

• In thyroid patients on L-T4 therapy (WATTS population):
  • DIO1 snp rs11206244 Average fT3: fT4 ratios = Major homozygous: 0.193; Heterozygous: 0.186; Minor homozygous: 0.175
  • DIO1 snp rs2235544 Average fT3: fT4 ratios = Major homozygous (AA) 0.177; Heterozygous (AC) 0.189; Minor homozygous (CC) 0.196

How different are the ratios above from people who are not on L-T4 therapy?

• “The fT₃/fT₄ ratio in the WATTS population [on L-T4 monotherapy] is significantly lower than in the populations with normal thyroid function, which is consistent with previous findings in patients on T₄ therapy who have a higher fT₄ and lower fT₃ for the same TSH due to lack of thyroid T₃ production.”
• The fT3:fT4 ratio in other cohorts averaged between 0.30 and 0.38

What about the DIO2 and DIO3 polymorphisms?

• Free T3 levels in _serum_ were not affected by polymorphisms in these other genes’ SNPs, at least the ones included in the study.

How can lower ratios of T3 to T4 in the bloodstream affect health?

• “Discovery of a marker that alters the ratio of circulating T₃ to T₄ may help us answer important questions about thyroid hormone action in humans.”
• In blood, “circulating concentrations of both T₃ and T₄ levels contribute to intracellular T₃ levels” in organs and tissues.
• T3 in blood has different effects on different organs, depending on how much that organ depends on serum for its source of T3. For example, “serum T₃ contributes 87% of intracellular T₃ in the kidney but only 50% in the pituitary and just 20% in the cerebral cortex.” In those organs, the remainder of T3 they need is achieved locally, within tissues and cells, by conversion of T4 into T3 via D2.
• “Hence, variation in the ratio of T₃ to T₄ in the circulation is likely to have different effects in different tissues, with potential impact on a wide range of important biological parameters such as body weight, serum lipids, heart rate, bone metabolism, central nervous system development, and psychological well-being.”

Why doesn’t this change the TSH?

• “TSH levels correlate as well if not better with serum fT₄ than fT₃ in patients on T₄“
• TSH gets mixed messages when one thyroid hormone is low and the other is high. “for the pituitary, the rise in circulating concentrations of fT₃ compensates for the fall in fT₄“
• The pituitary gland depends on serum levels of T3 for only 50% its own supply.  The rest of its T3 supply comes from converting T4 into T3 within its own tissues.

See our own discussion of these issues

• Rationale: The T3:T4 ratio
• Rationale: Low TSH in hypothyroidism
• Rationale: Free T3 testing