rs11206244 — DIO1 C785T

The Type 1 Deiodinase Variant That Shifts Your Thyroid Balance

Your body maintains thyroid hormone balance through a carefully orchestrated system of activation and inactivation. Type 1 deiodinase¹¹ Type 1 deiodinase
The DIO1 enzyme, primarily expressed in liver, kidney, and thyroid tissue (D1) is one of three enzymes that regulate this process, converting the inactive thyroid hormone T4 into active T3, while also clearing reverse T3 (rT3), an inactive metabolite. The rs11206244 variant, located in the 3' untranslated region²² 3' untranslated region
This regulatory region of the gene affects mRNA stability and protein production without changing the amino acid sequence of the DIO1 gene, influences how efficiently your body performs this conversion.

The Mechanism

This variant sits in the 3' UTR of the DIO1 gene at position 785 of the cDNA sequence.

The rs11206244 polymorphism is located in the mRNA's 3'-untranslated region of DIO1 gene , a regulatory area that can affect mRNA stability³³ mRNA stability
The 3' UTR contains signals that influence how long the mRNA molecule persists in the cell and how efficiently it is translated into protein and potentially protein production.

Carriers of the DIO1-785T allele had 3.8% higher FT4 and 14.3% higher rT3 levels, resulting in a lower T3/T4 and T3/rT3 ratio and a higher rT3/T4 ratio . This pattern is consistent with reduced D1 enzymatic activity—less efficient conversion of T4 to T3 and slower clearance of rT3.

The exact molecular mechanism remains under investigation.

As both SNPs are located in the 3'-UTR, it has been speculated whether the mRNA stability would be compromised or affect mRNA folding, which is necessary for the incorporation of Sec in the catalytic center of the protein . D1 is a selenoprotein containing the rare amino acid selenocysteine at its active site, and proper mRNA folding is essential for its incorporation.

The Evidence

Multiple large studies have consistently replicated the association between rs11206244 and thyroid hormone levels. A landmark study in healthy Danish twins⁴⁴ A landmark study in healthy Danish twins
van der Deure et al. The effect of genetic variation in the type 1 deiodinase gene on the interindividual variation in serum thyroid hormone levels. Clinical Endocrinology 2009 with 1,192 participants found that carriers of the D1-785T allele had 3.8% higher FT4 and 14.3% higher rT3 levels, resulting in a lower T3/T4 and T3/rT3 ratio and a higher rT3/T4 ratio, and this polymorphism explained 0.87% and 1.79%, respectively, of the variation in serum FT4 and rT3 . Importantly, TSH levels remained unaffected, suggesting the body compensates through feedback mechanisms.

A comprehensive study by Panicker et al.⁵⁵ A comprehensive study by Panicker et al.
Panicker et al. A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. Journal of Clinical Endocrinology and Metabolism 2008 examined deiodinase gene variants in multiple cohorts and two SNPs in the DIO1 gene, rs2235544 and rs11206244, were associated with fT3/fT4 ratio at P < 0.01 . The rs11206244 and rs2235544 variants are in linkage disequilibrium⁶⁶ linkage disequilibrium
These genetic variants tend to be inherited together, though rs2235544 appears to be the primary driver of the association (r² = 0.41).

Clinically, the tightly linked rs11206244T and rs2235544A alleles have been associated with lower enzymatic activity, and carriers of the variant rs11206244T and rs2235544A alleles show reduced serum concentrations of free T3 and higher concentrations of free T4 and free rT3, but no effect on serum TSH concentration .

An interesting study on antidepressant response⁷⁷ An interesting study on antidepressant response
Cooper-Kazaz et al. Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. American Journal of Psychiatry 2009 found that

DIO1-758T allele carriers had enhanced response to T3 supplementation with sertraline, with HRSD-21 scores declining by 68.7% over 8 weeks compared to 42.9% among non-carriers , suggesting that T carriers may benefit more from T3 supplementation.

Practical Implications

The clinical significance of this variant is nuanced. Multiple studies examining levothyroxine (T4) dose requirements in hypothyroid patients have found no significant association with polymorphisms in genes encoding the D1 and D2 enzymes, namely rs11206244 and rs2235544 in DIO1 .

The rs11206244 (C785T) SNP of DIO1 gene has no impact on the T3 and T4 hormones levels, and could have no contribution to the therapeutic response to LT4 in some populations.

However, the variant does affect thyroid hormone ratios.

Both TSH and rT3 were elevated in the carriers of T allele, though there were no significant differences in T3, T4 hormones among the three groups .

This SNP could have an impact on controlling the levels of rT3, and the effect may be more accurately reflected by the molar ratios of T3/rT3 and rT3/T4 than by the blood thyroid hormone levels .

This means that if you carry the T allele and are on thyroid hormone replacement, you may have normal TSH but still feel suboptimal if your T3/T4 ratio is low. Some patients with the T allele variant may benefit from combination T4/T3 therapy rather than T4 monotherapy, though this should be individualized and monitored by a healthcare provider.

Interactions

This variant is in moderate linkage disequilibrium with rs2235544 (another DIO1 variant), and the two tend to be inherited together. The combination of DIO1 variants may have compound effects on thyroid hormone metabolism. Additionally, other deiodinase genes (DIO2, DIO3) and thyroid hormone transporter genes can influence overall thyroid hormone status, and genetic testing across multiple loci may provide a more complete picture for individuals with persistent symptoms despite thyroid hormone replacement.