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Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function.

Abstract：

: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 approximately 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 muIU/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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Arnaud-Lopez L,Usala G,Ceresini G,Mitchell BD,Pilia MG,Piras MG,Sestu N,Maschio A,Busonero F,Albai G,Dei M,Lai S,Mulas A,Crisponi L,Tanaka T,Bandinelli S,Guralnik JM,Loi A,Balaci L,Sole G,Prinzis A,Mariotti S,

doi

10.1016/j.ajhg.2008.04.019

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

1270-80

issue

6

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(08)00307-8

journal_volume

82

pub_type

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