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 T3 receptor β (TRβ) 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 T4, free T4, T3, rT3, 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: TRβ-T/C (T = 96.8%, C = 3.2%). D1a-T was associated in a dose-dependent manner with a higher plasma rT3 [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 rT3/T4 (P = 0.01), and a lower T3/rT3 (P = 0.003) ratio. The D1b-G allele was associated with lower plasma rT3/T4 (P = 0.024) and with higher T3/rT3 (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 T4 (P = 0.06), TSH/T3 (P = 0.06), and TSH/T4 (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.