|(C;C)||3||1.3-1.79x risk of osteoarthritis, 3.75x bipolar, etc.|
|(C;T)||1.5||1.3-1.79x risk of osteoarthritis, 1.6x bipolar, etc.|
|qualified_impact||Insufficiently evaluated not reviewed|
rs225014, also known as Thr92Ala, represents a variant in the deiodinase, iodothyronine, type II DIO2 gene on chromosome 14. In dbSNP orientation for this SNP, the more common (T) allele encodes the Thr (threonine) and the somewhat less common (C) allele encodes the Ala (alanine) at this position in the DIO2 protein.
Polymorphisms in this SNP have associations with various conditions in the literature: osteoarthritis, psychological disorders, reduced thyroid hormone metabolism, Type 2 diabetes, and various other conditions.
[PMID 22492780] A 2012 article titled "Increased type II deiodinase protein in OA-affected cartilage and allelic imbalance of OA risk polymorphism rs225014 at DIO2 in human OA joint tissues" identified that the minor 'C' allele was associated with a significant, 1.3-fold higher risk of osteoarthritis (OA) relative to the 'T' allele.
[PMID 18334578] A 2008 article titled "Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis" explained that "Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval (CI) 1.37-2.34 with P = 2.02 x 10(-5) in female cases with advanced/symptomatic hip osteoarthritis." (Abstract)
[PMID 26098717] Association of the DIO2 gene single nucleotide polymorphisms with recurrent depressive disorder.. Published 2015. Abstract stated "The specific variant of the DIO2 gene, namely the CC genotype of the Thr92Ala polymorphism, was more frequently found in healthy subjects than in patients with depression, what suggests that it could potentially serve as a marker of a lower risk for recurrent depressive disorder. The distribution of four haplotypes was also significantly different between the two study groups with the TC (Thr-Gly) haplotype more frequently detected in patients with depression." (Abstract)
[PMID 19427350] Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population. Published 2009. This study analyzed "(ORFa)-Gly3Asp (rs12885300) and Thr92Ala (rs225014) with potential functions on the activity of DIO2." Findings in abstract: "Both SNPs were significantly higher in the BPAD (Bipolar disorder) patients, with odds ratios of 1.489 ... and 1.616 ... respectively. Individuals with two copies of the variant 3Gly or 92Ala were at greater risk of BPAD.... Haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for BPAD with odds ratios of 3.759 (95% CI=2.013-7.020) and 1.292 (95% CI=1.017-1.642), respectively, while ORFa-3Asp-92Thr probably played a protective role with an odds ratio of 0.395 (95% CI=0.284-0.549)." (Abstract)
Thyroid hormone metabolism and treatment for hypothyroidism
[PMID 19190113]. According to a 2009 study of 500 patients, hypothyroid patients on LT4 (Levothyroxine) therapy who don't show much improvement may have lower brain thyroid levels (not reflected in their serum levels) correlated to the number of rs225014(C) alleles they carry, and these patients may benefit from combined levothyroxine and liothyronine therapy.
"The Thr92AlaD2 Polymorphism May Play a Novel Role in Hypothyroidism" by Elizabeth A McAninch, Antonio C Bianco, US Endocrinology, 2015;11(2):92–4 DOI: http://doi.org/10.17925/USE.2015.11.02.92. This article stated "A prevalent polymorphism in D2, Thr92AlaD2, has been associated with improved well-being on “combination therapy” with T4+T3; the underlying mechanism is unclear as T4-to-T3 conversion appears normal. Novel studies indicate this might be a risk factor for neurodegenerative disease. If the relationship between Thr92AlaD2-expression and treatment preference is confirmed, personalized medicine may play a role in hypothyroidism." (Abstract)
However, as of 2016, controversy continued about the value of testing for and treating polymorphisms of this SNP. See the liothyronine page for further references.
Type 2 Diabetes
[PMID 20566590] Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis. Published 2010
[PMID 20930717] D2 Thr92Ala and PPARgamma2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients.. Published 2011. Abstract stated "Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMA(IR) index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms on HOMA(IR) index, with carriers of both D2 Ala/Ala genotype and PPARγ2 Ala12 allele showing the highest HOMA(IR) values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010)."
[PMID 21685153] Type 2 deiodinase and host responses of sepsis and acute lung injury.. Published 2011. Abstract stated: "The G (Ala) allele of the Thr92Ala coding single-nucleotide polymorphism (rs225014) was protective in severe sepsis and severe sepsis-associated ALI after adjustments for age, sex, and genetic ancestry in a logistic regression model in European Americans."
[PMID 19352319] Novel insights into thyroid hormones from the study of common genetic variation.. Published 2009. Abstract stated "studies of type 2 iodothyronine deiodinase (D2) variants have shown that thyroid hormones contribute to osteoarthritis and these variants influence Intelligence quotient alterations associated with iodine deficiency."
[PMID 15286152] Positive association of the DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China.. Published 2004