rs225014 — DIO2 Thr92Ala

DIO2 Thr92Ala — Why Some People Need T3 Instead of T4 Alone

Your thyroid gland secretes mostly T4 (thyroxine), an inactive prohormone that must be converted to T3 (triiodothyronine) to exert biological effects. This conversion happens locally in tissues¹¹ This conversion happens locally in tissues
The brain derives up to 80% of its intracellular T3 from circulating T4 through local conversion via the type 2 deiodinase (DIO2) enzyme. The Thr92Ala variant changes a threonine to alanine at position 92 of the DIO2 protein, reducing enzyme activity by approximately 20%²² reducing enzyme activity by approximately 20%
Panicker et al. J Clin Endocrinol Metab 2009 and altering its cellular behavior. This common variant affects roughly 36% of people of European ancestry³³ roughly 36% of people of European ancestry
Present in 11-16% as CC homozygotes and has become a focal point in debates about optimal thyroid hormone replacement therapy.

The Mechanism

The wild-type Thr92 version of DIO2 normally resides in the endoplasmic reticulum, where it efficiently converts T4 to T3. The Ala92 variant protein has a longer half-life⁴⁴ The Ala92 variant protein has a longer half-life
Mislocalized to the Golgi apparatus and accumulates in the Golgi apparatus rather than the ER. This ectopic localization disrupts normal cellular function and reduces the efficiency of T4-to-T3 conversion⁵⁵ reduces the efficiency of T4-to-T3 conversion
Castagna et al. demonstrated lower T3 levels in muscle and thyrotrophs, particularly in tissues that rely heavily on local T3 production like the brain and pituitary gland. Because DIO2 activity in the hypothalamus and pituitary regulates TSH secretion through negative feedback, the variant can create a mismatch: normal serum TSH and T4 levels may mask inadequate tissue-level T3, especially in the central nervous system.

The Evidence

The landmark study establishing clinical relevance of this variant analyzed 552 hypothyroid patients on levothyroxine (T4) monotherapy⁶⁶ 552 hypothyroid patients on levothyroxine (T4) monotherapy
Panicker et al. J Clin Endocrinol Metab 2009. The CC genotype was present in 16% of participants and was associated with worse baseline psychological well-being scores⁷⁷ worse baseline psychological well-being scores
14.1 vs 12.8 on GHQ-12, P=0.03 compared to TT carriers. More importantly, CC carriers showed greater improvement on T4+T3 combination therapy⁸⁸ greater improvement on T4+T3 combination therapy
2.3 GHQ points at 3 months, P=0.03 compared to T4 alone, despite no differences in serum thyroid hormone levels between genotypes.

A Danish randomized controlled trial of 45 hypothyroid patients⁹⁹ Danish randomized controlled trial of 45 hypothyroid patients
Carle et al. Eur Thyroid J 2017 found that preference for T4+T3 combination therapy increased in a dose-dependent manner with genetic burden: 42% preferred combination therapy with no polymorphisms, 63% with one polymorphism (DIO2 or MCT10), and 100% with both¹⁰¹⁰ 42% preferred combination therapy with no polymorphisms, 63% with one polymorphism (DIO2 or MCT10), and 100% with both
p=0.009 for trend. This suggests the DIO2 variant has a measurable, though incomplete, effect on treatment satisfaction.

In thyroidectomized patients on levothyroxine replacement¹¹¹¹ thyroidectomized patients on levothyroxine replacement
Porcelli et al. J Clin Endocrinol Metab 2017, carriers of the Thr92Ala variant showed significantly lower serum free T3 levels¹²¹² significantly lower serum free T3 levels
34.3% had reduced FT3 despite normal TSH compared to wild-type patients, providing biochemical confirmation that the variant impairs systemic T4-to-T3 conversion. However, not all studies show associations: [a Dutch population study of over 1,000 individuals | Wouters et al. Thyroid 2017] found no association with thyroid hormone levels or quality of life in the general population, suggesting the variant's effects may be most apparent in patients who lack endogenous thyroid function.

Beyond thyroid therapy, the variant has been linked to higher body mass index, insulin resistance, and type 2 diabetes¹³¹³ higher body mass index, insulin resistance, and type 2 diabetes
Multiple studies in diverse populations, suggesting DIO2 activity influences metabolic regulation. Associations have also been reported with osteoarthritis, bipolar disorder, and schizophrenia¹⁴¹⁴ osteoarthritis, bipolar disorder, and schizophrenia
DIO2 is expressed in growth plate cartilage and multiple brain regions.

Practical Implications

If you're on levothyroxine (T4) monotherapy and still experience fatigue, weight gain, brain fog, or mood disturbances¹⁵¹⁵ fatigue, weight gain, brain fog, or mood disturbances
Common persistent symptoms in euthyroid patients despite normal TSH levels, the Thr92Ala variant could be contributing. The evidence supports considering T4+T3 combination therapy for C-allele carriers who remain symptomatic. Current guidelines suggest an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight¹⁶¹⁶ an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight
European Thyroid Association guidelines, with T3 typically split into two daily doses due to its shorter half-life.

Testing for this variant can be useful before thyroidectomy to anticipate which patients may struggle with T4 monotherapy. However, genetic testing is not widely available through standard medical channels; historically, 23andMe included rs225014 on their v3 and v4 chips, but it was removed from the v5 chip¹⁷¹⁷ it was removed from the v5 chip
No longer genotyped as of 2017. Specialized laboratories like Regenerus Labs offer targeted DIO2 genotyping.

For those with hypothyroidism who are not on thyroid medication, ensuring adequate selenium and iodine intake¹⁸¹⁸ selenium and iodine intake
DIO2 is a selenoprotein requiring selenium for function supports whatever DIO2 enzyme activity remains. However, dietary interventions alone are unlikely to fully compensate for reduced enzyme efficiency in homozygous C-allele carriers.

Interactions

The DIO2 variant interacts with rs17606253 in the MCT10 gene, which encodes a thyroid hormone transporter. The Danish RCT showed that patients with both polymorphisms had 100% preference for T4+T3 combination therapy¹⁹¹⁹ The Danish RCT showed that patients with both polymorphisms had 100% preference for T4+T3 combination therapy
Carle et al. 2017, suggesting the combination creates a more severe impairment in cellular thyroid hormone availability than either variant alone. This makes biological sense: MCT10 transports thyroid hormones into cells, and DIO2 converts T4 to T3 once inside; defects in both steps compound the problem.

Another variant within the DIO2 gene, rs12885300 (ORFa-Gly3Asp), has been studied alongside Thr92Ala in several trials. While less consistently associated with clinical outcomes, it may modulate DIO2 expression levels and has been linked to body weight changes after Graves' disease treatment²⁰²⁰ linked to body weight changes after Graves' disease treatment
Combined analysis shows additive effects.

Compound implication for DIO2 Thr92Ala + MCT10 rs17606253: Individuals carrying both the DIO2 C allele (CT or CC) and the MCT10 variant may experience more pronounced difficulties with T4 monotherapy and show the strongest preference for T4+T3 combination treatment. If you match this profile and have persistent hypothyroid symptoms despite normal TSH on levothyroxine, discuss combination therapy with your endocrinologist, citing the Carle et al. 2017 study.