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

被引：106

作者：

Arnaud-Lopez, Lisette ^{[10
]}

Usala, Gianluca ^{[1
]}

Ceresini, Graziano ^{[2
]}

Mitchell, Braxton D. ^{[3
]}

Pilia, Maria Grazia ^{[1
]}

Piras, Maria Grazia ^{[1
]}

Sestu, Natascia ^{[1
]}

Maschio, Andrea ^{[1
]}

Busonero, Fabio ^{[1
]}

Albai, Giuseppe ^{[1
]}

Dei, Mariano ^{[1
]}

Lai, Sandra ^{[1
]}

Mulas, Antonella ^{[1
]}

Crisponi, Laura ^{[1
]}

Tanaka, Toshiko ^{[4
]}

Bandinelli, Stefania ^{[5
]}

Guralnik, Jack M. ^{[6
]}

Loi, Angela ^{[1
]}

Balaci, Lenuta ^{[1
]}

Sole, Gabriella ^{[1
]}

Prinzis, Alessia ^{[7
]}

Mariotti, Stefano ^{[7
]}

Shuldiner, Alan R. ^{[3
,8
]}

Cao, Antonio ^{[1
]}

Schlessinger, David ^{[10
]}

Uda, Manuela ^{[1
]}

Abecasis, Goncalo R. ^{[9
]}

Nagaraja, Ramaiah ^{[10
]}

Sanna, Serena ^{[1
]}

Naitza, Silvia ^{[1
]}

机构：

[1] CNR, Ist Neurogenet & Neurofarmacol, I-09042 Cagliari, Italy

[2] Univ Parma, Dept Internal Med, Sect Geriatr, I-43100 Parma, Italy

[3] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[4] NIA, Clin Res Branch, Baltimore, MD 21225 USA

[5] ASF, Geriatr Rehabil Unit, I-50125 Florence, Italy

[6] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA

[7] Univ Cagliari, Dept Med Sci M Aresu, I-09042 Cagliari, Italy

[8] Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21201 USA

[9] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[10] NIA, Genet Lab, Baltimore, MD 21224 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2008年 / 82卷 / 06期

关键词：

D O I：

10.1016/j.ajhg.2008.04.019

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1270 / 1280

页数：11

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