Peeters Robin P, van Toor Hans, Klootwijk Willem, de Rijke Yolanda B, Kuiper George G J M, Uitterlinden Andre G, Visser Theo J
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, 3000 DR The Netherlands.
J Clin Endocrinol Metab. 2003 Jun;88(6):2880-8. doi: 10.1210/jc.2002-021592.
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.
参与甲状腺激素代谢的基因中的单核苷酸多态性（SNP）可能会影响甲状腺激素的生物活性。我们研究了脱碘酶（D1 - D3）、促甲状腺激素受体（TSHR）和T（3）受体β（TRβ）基因中SNP的发生情况及其可能的影响。通过公共数据库或对15名随机选择的受试者（30个等位基因）的基因组DNA进行测序来鉴定SNP。在156名健康献血者中确定了所鉴定SNP的基因型，并将其与血浆T（4）、游离T（4）、T（3）、反T（3）和TSH水平相关联。鉴定出8个感兴趣的SNP，其中4个尚未发表。3个位于3'-非翻译区：D1a - C/T（等位基因频率，C = 66%，T = 34%）、D1b - A/G（A = 89.7%，G = 10.3%）和D3 - T/G（T = 85.5%，G = 14.2%）。4个是错义SNP：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%）和TSHRc - C/G（Asp727Glu，Asp = 90.7%，Glu = 9.3%）。1个是沉默SNP：TRβ - T/C（T = 96.8%，C = 3.2%）。D1a - T与较高的血浆反T（3）呈剂量依赖性相关[CC，0.29±0.01；CT，0.32±0.01；TT，0.34±0.02 nmol/升（平均值±标准误）；P = 0.017]，较高的血浆反T（3）/T（4）（P = 0.01），以及较低的T（3）/反T（3）（P = 0.003）比值。D1b - G等位基因与较低的血浆反T（3）/T（4）（P = 0.024）和较高的T（3）/反T（3）（P = 0.08）比值相关。TSHRc - G与较低的血浆TSH相关（CC，1.38±0.07，vs. GC，1.06±0.14 mU/升；P = 0.04），以及较低的血浆TSH/游离T（4）（P = 0.06）、TSH/T（3）（P = 0.06）和TSH/T（4）（P = 0.08）比值。其他SNP与TSH和碘甲状腺原氨酸水平未发现关联。我们分析了5个甲状腺激素途径基因中的8个SNP，发现在正常人群中，2个基因（Dl、TSHR）中的3个SNP与血浆TSH或碘甲状腺原氨酸水平存在显著关联。
