||Risk of significantly decreased T4-T3 thyroid conversion, may worsen bone loss, brain effects
||Risk of decreased thyroid hormone metabolism in peripheral tissues
||no increased risk of thyroid hormone metabolism problems
||Thyroid hormone levels
||A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.
||.13 [0.1-0.16] unit increase
[PMID 18492748] A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. (Published 2008) Researchers noted that reduced fT3/fT4 ratios may be significant, since various bodily tissues and organs differ in their level of dependence on fT3 and fT4. They analyzed 18 SNPs of DIO1, DIO2, and DIO3 and measured thyroid hormone levels in 552 people on L-T4 hormone replacement therapy, and three healthy control groups not on L-T4 therapy (totalling 2513 people). Analysis was adjusted for age and sex.
- Among patients, the _minor_ allele of rs11206244 was associated with reduced fT3:fT4 ratio from 0.193 in Common homozygous to 0.175 in Minor homozygous (-0.18) p for trend = 0.004).
- Among patients, the _major_ allele of rs2235544 was associated with reduced fT3:fT4 ratio (from 0.196 in Minor homozygous to 0.177 in Common homozygous (-.019), p for trend = 0.01).
- The two SNPs rs2235544 and rs11206244, were in linkage disequilibrium (LD) (r2 = 0.41), and rs2235544 was driving the association.
- Polymorphisms of rs2235544 in both cases and controls achieved genome-wide significance for effect on fT3/fT4 ratio(p=3.6x10-13) in the general population, each minor allele increasing the ratio by 0.2SD.
- Polymorphism did not affect TSH levels.
- None of the SNPs in the other deiodinase genes DIO2 DIO3 influenced T3, T4 or TSH serum levels.
- Reverse T3 (rT3) levels were not studied.
- Regardless of the polymorphism of rs2235544, the fT3:fT4 ratio and fT3 levels were consistently and significantly lower in hypothyroid patients on L-T4 therapy than in healthy controls, and patients' mean TSH was also lower than in controls.
[PMID 24910925] A 2014 study "Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer" confirmed an earlier study's finding of LD (linkage disequilibrium) between rs11206244 T and rs2235544 A in DIO1.
[PMID 23408906] A 2013 study "A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function" explained that "even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders." (Abstract). The study focused on genome-wide association data in 26,420 euthyroid (healthy, not hypothyroid or hyperthyroid) individuals phenotyped for serum TSH and 17,520 for FT4 levels. The meta-analysis highlighted a list of 26 SNPs from a wide variety of genes.
- For DIO1 rs2235544 A/C, the A allele (51% frequency) was associated with an increase in FT4 levels, with a slightly larger effect on males than females.
[PMID 18815314] Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling.. This 2008 review discussed findings from previous research. The C allele of rs2235544 was associated with increased D1 function and increased FT3/T4 ratio.
[PMID 29134650] Thyroid associated genetic polymorphisms in relation to breast cancer risk in the Malmö Diet and Cancer Study.
[PMID 31452060] Common genetic variations of deiodinase genes and prognosis of brain tumor patients.