Polymorphisms in Thyroid Hormone Pathway Genes Are Associated with Plasma TSH and Iodothyronine Levels in Healthy Subjects

Abstract

Single nucleotide polymorphisms (SNPs) in genes involved in thyroid hormone metabolism may affect thyroid hormone bioactivity. We investigated the occurrence and possible effects of SNPs in the deiodinases (D1-D3), the TSH receptor (TSHR), and the T(3) receptor beta (TR beta) genes. SNPs were identified in public databases or by sequencing of genomic DNA from 15 randomly selected subjects (30 alleles). Genotypes for the identified SNPs were determined in 156 healthy blood donors and related to plasma T(4), free T(4), T(3), rT(3), and TSH levels. Eight SNPs of interest were identified, four of which had not yet been published. Three are located in the 3'-untranslated region: D1a-C/T (allele frequencies, C = 66%, T = 34%), D1b-A/G (A = 89.7%, G = 10.3%), and D3-T/G (T = 85.5%, G = 14.2%). Four are missense SNPs: D2-A/G (Thr92Ala, Thr = 61.2%, Ala = 38.8%), TSHRa-G/C (Asp36His, Asp = 99.4%, His = 0.6%), TSHRb-C/A (Pro52Thr, Pro = 94.2%, Thr = 5.8%), and TSHRc-C/G (Asp727Glu, Asp = 90.7%, Glu = 9.3%). One is a silent SNP: TR beta-T/C (T = 96.8%, C = 3.2%). D1a-T was associated in a dose-dependent manner with a higher plasma rT(3) [CC, 0.29 +/- 0.01; CT, 0.32 +/- 0.01; and TT, 0.34 +/- 0.02 nmol/liter (mean +/- SE); P = 0.017], a higher plasma rT(3)/T(4) (P = 0.01), and a lower T(3)/rT(3) (P = 0.003) ratio. The D1b-G allele was associated with lower plasma rT(3)/T(4) (P = 0.024) and with higher T(3)/rT(3) (P = 0.08) ratios. TSHRc-G was associated with a lower plasma TSH (CC, 1.38 +/- 0.07, vs. GC, 1.06 +/- 0.14 mU/liter; P = 0.04), and with lower plasma TSH/free T(4) (P = 0.06), TSH/T(3) (P = 0.06), and TSH/T(4) (P = 0.08) ratios. No associations with TSH and iodothyronine levels were found for the other SNPs. We have analyzed eight SNPs in five thyroid hormone pathway genes and found significant associations of three SNPs in two genes (D1, TSHR) with plasma TSH or iodothyronine levels in a normal population.

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…In addition, this SNP is associated with higher serum TSH but not thyroid hormone levels in healthy individuals (128) and with lower T3 release after TRH infusion (129). However, this change was not correlated with differences in general well-being, cognitive function or the response to therapy with T3+T4 in hypothyroid patients in same study, but not in others (130,131).…”

Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study

“…In this context it is interesting that a recently identified polymorphism in the gene coding for the type two deiodinase, the enzyme responsible for the regulation of T 3 availability to the tissues, has been proposed in order to help identifying subgroups more likely to benefit from T 4 /T 3 combination therapy (23). Another polymorphism, located in OATP1C1, a thyroid hormone transporter expressed at the blood-brain barrier, has been associated with fatigue and depression (24).…”

A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels

“…The causative genes are, however, not well established. Well-known TH pathway genes such as the deiodinases (8)(9)(10)(11)(12), TSH receptor (10,13,14) and TH transporters (15)(16)(17) have been associated with TH serum levels, but their contribution to the overall variation is modest (12,13). A genome-wide linkage scan by Panicker et al (18) identified eight chromosomal loci involved in the control of the pituitarythyroid axis, but as can be expected from this type of study, the actual genes were not identified.…”