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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 6 2880-2888
Copyright © 2003 by The Endocrine Society

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

Robin P. Peeters, Hans van Toor, Willem Klootwijk, Yolanda B. de Rijke, George G. J. M. Kuiper, Andre G. Uitterlinden and Theo J. Visser

Departments of Internal Medicine (R.P.P., H.v.T., W.K., Y.B.d.R., G.G.J.M.K., A.G.U., T.J.V.), Clinical Chemistry (Y.B.d.R., A.G.U.), and Epidemiology and Biostatistics (A.G.U.), Erasmus University Medical Center, Rotterdam, 3000 DR The Netherlands

Address all correspondence and requests for reprints to: Theo J. Visser, Ph.D., Department of Internal Medicine, Room Bd 234, Erasmus University Medical Center, P.O. Box 1738, 3000DR Rotterdam, The Netherlands. E-mail: visser{at}inw3.azr.nl.

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 ß (TRß) 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: TRß-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.

This work was supported by ZonMw Grant 920-03-146 (to R.P.P.).

Abbreviations: D1–D3, Deiodinases; dbEST, EST database; dbSNP, SNP database; DTT, dithiothreitol; EST, expressed sequence tag; FT4, free T4; ORD, outer ring deiodination; RFLP, restriction fragment length polymorphism; SBE, single base extension; SeC, selenocysteine; SECIS, SeC insertion sequence; SNP, single nucleotide polymorphism; TRß, T3 receptor ß; TSHR, TSH receptor; UTR, untranslated region; WT, wild-type.




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