Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function.
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.
Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
Lisette
L
Arnaud-Lopez
Gianluca
G
Usala
Graziano
G
Ceresini
Braxton D
BD
Mitchell
Maria Grazia
MG
Pilia
Maria Grazia
MG
Piras
Natascia
N
Sestu
Andrea
A
Maschio
Fabio
F
Busonero
Giuseppe
G
Albai
Mariano
M
Dei
Sandra
S
Lai
Antonella
A
Mulas
Laura
L
Crisponi
Toshiko
T
Tanaka
Stefania
S
Bandinelli
Jack M
JM
Guralnik
Angela
A
Loi
Lenuta
L
Balaci
Gabriella
G
Sole
Alessia
A
Prinzis
Stefano
S
Mariotti
Alan R
AR
Shuldiner
Antonio
A
Cao
David
D
Schlessinger
Manuela
M
Uda
Gonçalo R
GR
Abecasis
Ramaiah
R
Nagaraja
Serena
S
Sanna
Silvia
S
Naitza
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D000242:Cyclic AMP / Q000378:metabolism; D005246:Feedback; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D013959:Thyroid Diseases / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D013961:Thyroid Gland / Q000201:enzymology* / Q000502:physiology*; D013972:Thyrotropin / Q000097:blood*; D013974:Thyroxine / Q000096:biosynthesis; D014284:Triiodothyronine / Q000096:biosynthesis
D014284:Triiodothyronine; D013972:Thyrotropin; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human; D013974:Thyroxine