It has been estimated that 40-60% of the variation of serum TSH levels is under genetic control. In keeping with this notion, polymorphisms of several genes potentially involved in the control of thyroid function have been linked to serum TSH concentrations. Genome-wide association scan (GWAS) is a powerful tool to simplify genetic analysis of complex traits and diseases. By genotyping >360,000 single nucleotide polymorphisms (SNP) in a large cohort of 4,300 Sardinian subjects, we recently identified a strong association (p = 1.3 x 10-11) between alleles of the SNP rs4704397 and serum TSH. This association was confirmed in two genetically unrelated cohorts from Tuscany and the Old Order Amish and contributed to the 2.3% of the total variation of circulating TSH concentration. The rs4704397 SNP is located in intron 1 of the phosphodiesterase 8B (PDE8B) gene, encoding a highaffinity cAMP-specific phosphodiesterase abundantly expressed in thyroid tissue. This suggests that different PDE8B variants may modulate c-AMP-dependent thyroid hormone secretion and affect by feed-back pituitary TSH production. So far at least one independent study confirmed that the minor A allele of the rs4704397 SNP is associated with higher serum TSH in a cohort of pregnant women. In conclusion PDE8B is an important gene involved in controlling serum TSH concentration in normal individuals. Further studies are needed to ascertain whether and to what extent PDE8B may also represent a candidate gene for thyroid dysfunction and/or response to treatment.
Phosphodiesterase 8B (PDE8B) gene variants and TSH levels
MARIOTTI, STEFANO;
2010-01-01
Abstract
It has been estimated that 40-60% of the variation of serum TSH levels is under genetic control. In keeping with this notion, polymorphisms of several genes potentially involved in the control of thyroid function have been linked to serum TSH concentrations. Genome-wide association scan (GWAS) is a powerful tool to simplify genetic analysis of complex traits and diseases. By genotyping >360,000 single nucleotide polymorphisms (SNP) in a large cohort of 4,300 Sardinian subjects, we recently identified a strong association (p = 1.3 x 10-11) between alleles of the SNP rs4704397 and serum TSH. This association was confirmed in two genetically unrelated cohorts from Tuscany and the Old Order Amish and contributed to the 2.3% of the total variation of circulating TSH concentration. The rs4704397 SNP is located in intron 1 of the phosphodiesterase 8B (PDE8B) gene, encoding a highaffinity cAMP-specific phosphodiesterase abundantly expressed in thyroid tissue. This suggests that different PDE8B variants may modulate c-AMP-dependent thyroid hormone secretion and affect by feed-back pituitary TSH production. So far at least one independent study confirmed that the minor A allele of the rs4704397 SNP is associated with higher serum TSH in a cohort of pregnant women. In conclusion PDE8B is an important gene involved in controlling serum TSH concentration in normal individuals. Further studies are needed to ascertain whether and to what extent PDE8B may also represent a candidate gene for thyroid dysfunction and/or response to treatment.
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