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This version published online on October 9, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-1298
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Submitted on June 19, 2009
Accepted on August 25, 2009

Phosphodiesterase 8B Gene Polymorphism Is Associated with Subclinical Hypothyroidism in Pregnancy

Beverley M. Shields, Rachel M. Freathy, Bridget A. Knight, Anita Hill, Michael N. Weedon, Timothy M. Frayling, Andrew T. Hattersley, and Bijay Vaidya*

Peninsula National Institute for Health Research Clinical Research Facility (B.M.S., B.A.K., A.H., A.T.H.), Peninsula Medical School, Exeter University, Exeter EX2 5DW, United Kingdom; Genetics of Complex Traits (R.M.F., M.N.W., T.M.F.), Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter University, Exeter EX1 2LU, United Kingdom; and Diabetes, Endocrinology, and Vascular Health Centre (B.V.), Royal Devon and Exeter National Health Service Foundation Trust, Exeter EX2 5DW, United Kingdom

* To whom correspondence should be addressed. E-mail: Bijay.Vaidya{at}pms.ac.uk.

Background: Maternal subclinical hypothyroidism is associated with a number of adverse outcomes in pregnancy. The Endocrine Society's recent consensus guidelines have recommended treatment with T4 for this condition in pregnancy. The single nucleotide polymorphism rs4704397 in the phosphodiesterase 8B (PDE8B) gene has been found to be associated with altered serum TSH concentrations in the general population. We aimed to assess whether genetic variation in TSH due to the rs4704397 genotype affects the number of individuals classified as having subclinical hypothyroidism in pregnancy.

Methods: Serum TSH, FT4, FT3, and thyroid peroxidase antibodies (TPOAbs) were measured in 970 pregnant women at 28 wk gestation. rs4704397 genotype was available on 877 subjects. Reference range calculations were based on the TPOAb-negative women.

Results: TSH, but not FT4, FT3, or TPOAbs, varied with genotype and was highest in those with the AA genotype (median, 2.16, 1.84, and 1.73 mIU/liter for AA, AG, and GG genotypes, respectively; P = 0.0004). A greater proportion of women with the AA genotype had TSH concentrations above 4.21 mIU/liter, the upper limit of the reference range, compared with the AG and GG genotypes (9.6 vs. 3.5%, respectively; P = 0.004). Maternal PDE8B genotype was not associated with offspring birthweight or gestational age at delivery.

Conclusion: Genetic variation in TSH levels in pregnancy associated with the PDE8B rs4704397 genotype has implications for the number of women treated for subclinical hypothyroidism under current guidelines. Consideration should be made to individualization of normal ranges, potential effects on pregnancy outcome, and intention to treat for subclinical hypothyroidism in pregnancy.






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