A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters; including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement

Objective Common variants in PDE8B are associated with TSH, but apparently without any effect on thyroid hormone levels which is difficult to explain. Furthermore the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine. Design Four cohorts were used (N=2,557) the Busselton Health Study (thyroid function measured on 2 occasions), DEPTH, EFSOCH (selective cohorts) and WATTS (individuals on levothyroxine). Methods Meta-analysis to clarify associations between the rs4704397 SNP in PDE8B on TSH, T3 and T4 levels. Results Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (p=1.64x10-10 0.20 SD/allele, 95%CI 0.142, 0.267) and identified a possible new association with free T4 (p=0.023, -0.07 SD/allele, 95% CI -0.137, -0.01) no association was seen with free T3 (p=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 SD/allele, 95%CI 0.04, 0.238) and 1994 (0.20 SD/allele, 95%CI 0.102, 0.300) and even more consistent between PDE8B and free T4 in 1981 (-0.068 SD/allele, 95% CI: -0.167, 0.031) and 1994 (-0.07 SD/allele, 95%CI: -0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on levothyroxine. Conclusion Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T4 levels that are consistent over time and lost in individuals on levothyroxine. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.