Endocrine Abstracts

Background: Single-nucleotide polymorphisms (SNPs) allow us to study effects of genetic variation on thyroid hormone levels. Phosphodiesterase 8B (PDE8B) is a protein responsible for cAMP generation, found in thyroid and brain tissue, but not normal pituitary tissue. Variation at this locus has been reported to influence TSH levels, but its effect on T₃ and T₄ had not been studied in the general population. Deiodinase 1 (DIO1) is known to influence T₄ and T₃/T₄ ratio, but not TSH levels. We examined the effect of SNPs rs4704397 (PDE8B) and rs2235544 (DIO1) on serum thyroid hormone levels.

Methods: We studied 917 patients with thyroid hormone levels in the reference range. Thyroid function was measured on two occasions in 1981 and 1995 from the Busselton Health Study (T₃ not measured in 1981).

Results: TSH varied by PDE8B genotype, highest in the AA genotype P=7.08×10⁻⁶ (1981) P=8.03×10⁻⁶ (1995) causing a TSH rise equal to 0.26 S.D. Variation in PDE8B had no effect on serum T₃ and T₄ concentrations. Variation in DIO1 genotype had no effect on TSH but affected T₄ levels, P=0.016 (1981) and P=0.001 (1995), with greatest effect seen on T₃/T₄ ratio P=5.93×10⁻⁴ (1995).

Conclusion: We confirmed the effect of PDE8B on TSH and DIO1 on serum T₄ and serum T₃/T₄ ratio. Surprisingly there was no effect of PDE8B on T₃ and T₄ levels. Rather than influencing intrinsic thyroid hormone production variation in PDE8B appears to alter an individual’s ‘set point’ for TSH. There is no effect of DIO1 variation on TSH levels implying that the alteration in T₄ and T₃/T₄ ratio is perceived by the brain as ‘neutral.’ This study highlights that common genetic variation can affect different aspects of the thyroid hormone pathway, independently from each other.