Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid
Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid
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DOI：
10.1016/j.ajhg.2008.04.019
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发表时间：
2008-06-01
影响因子：
9.8
通讯作者：
Naitza, Silvia
中科院分区：
文献类型：
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作者：
Arnaud-Lopez, Lisette;Usala, Gianluca;Naitza, Silvia
促甲状腺激素（TSH）通过结合其G蛋白偶联受体（TSHR）和产生环AMP （cAMP）来控制甲状腺的生长和激素分泌。血清TSH是甲状腺功能的敏感指标，甲状腺功能的明显异常会导致常见的内分泌紊乱，影响大约10%的人的一生。通过对4300名撒丁岛人的362129个snp进行基因分型，我们发现rs4704397等位基因与循环TSH水平之间存在很强的相关性（p = 1.3 x 10(-11)）；小A等位基因每增加一个拷贝，TSH升高0.13 mu IU/ml。单核苷酸多态性（SNP）位于PDE8B的内含子1上，编码一种高亲和力的camp特异性磷酸二酯酶。这种关联在4158个人中得到了重复，包括额外的撒丁人和来自托斯卡纳和旧秩序阿米什的两个遗传上遥远的队列（总体p值= 1.9 x 10(-20)）。除了TSH水平与PDE8B snp的关联外，我们的基因组扫描在24个基因的集中分析中提供了与PDE10A和几个生物学上有趣的候选基因的关联的证据。特别是，我们发现了TSH水平与THRB （rs1505287, p = 7.3 × 10(-5)）、GNAQ （rs10512065, p = 2.0 × 10(-4)）、TG （rs2252696, p = 2.2 × 10(-3)）、POU1F1 （rs1976324, p = 3.9 × 10(-3)）、PDE4D （rs27178, p = 8.3 × 10(-3)）和TSHR （rs4903957, p = 8.6 × 10(-3)）位点的snp相关的证据。总的来说，结果表明PDE8B变异对甲状腺cAMP水平的主要影响。这会影响T4和T3的产生，并反馈到垂体改变TSH的释放。因此，PDE8B可能为治疗甲状腺功能障碍提供一个候选靶点。
Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting similar to 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 mu IU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction.