PDE8B rs4704397 Modifies the Association Between Iodine Status and Serum TSH in Pregnant Women

Background: Maternal thyroid function is essential for a healthy pregnancy, and elevated thyrotropin (TSH) is the hallmark of subclinical hypothyroidism (SCH). Previous studies have shown that both genetic factors, particularly the PDE8B rs4704397 polymorphism, and iodine intake influence TSH levels. However, whether iodine-related changes in TSH vary by genetic background remains unclear. This study aimed to investigate the association between iodine status and TSH levels across different genetic backgrounds in early pregnancy. Methods: We performed a retrospective analysis of prospectively collected data from the subclinical hypothyroid in early pregnancy (SHEP) prospective cohort, using a nested case-control design. The analysis included 728 pregnant women with SCH and 968 age- and body mass index-matched euthyroid controls. Participants were genotyped for PDE8B rs4704397 using matrix-assisted laser desorption ionization–time-of-flight mass spectrometry. The urinary iodine-to-creatinine ratio (UIC/Cr) was used to assess iodine status. Restricted cubic spline (RCS), linear, and logistic regression models were applied to evaluate the associations of UIC/Cr with TSH, free thyroxine (fT4), and SCH, stratified by PDE8B genotype. Results: The distribution of the AA genotype did not differ between case and control groups. In the overall population, the AA genotype accounted for 70% of participants. RCS analyses showed a positive linear association between UIC/Cr and serum TSH concentrations in both the overall population and individuals with the AA genotype, but not in those with the GA + GG genotypes. A nonlinear inverse association between UIC/Cr and fT4 levels was observed across all genotypes. Among individuals with the AA genotype, each standard deviation increase in UIC/Cr was associated with higher serum TSH levels (adjusted β = 0.16, confidence interval [CI]: 0.08–0.24) and an increased risk of SCH (OR = 1.22, CI: 1.08–1.39), but not among those with the GA + GG genotypes ( p for genotype × UIC/Cr interaction = 0.09 for both outcomes). In contrast, fT4 levels decreased with increasing UIC/Cr across all genotypes (p for genotype × UIC/Cr interaction = 0.48). Conclusions: Higher iodine status was associated with higher TSH levels and an increased risk of SCH only among pregnant women with the PDE8B rs4704397 AA genotype, suggesting that the effect of iodine on thyroid function is modified by genotype.