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The Association of Polymorphisms in the Type 1 and 2 Deiodinase Genes with Circulating Thyroid Hormone Parameters and Atrophy of the Medial Temporal Lobe

Departments of Epidemiology and Biostatistics (F.J.d.J., T.d.H., A.H., A.G.U., M.M.B.B.), Neurology (F.J.d.J., T.d.H.), Internal Medicine (R.P.P., W.M.v.d.D., A.G.U., T.J.V.), and Clinical Chemistry (A.G.U.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. Monique M. B. Breteler, Department of Epidemiology, Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. E-mail: m.breteler{at}erasmusmc.nl.

Context: Thyroid function has been related to Alzheimer disease (AD) and neuroimaging markers thereof. Whether thyroid dysfunction contributes to or results from developing AD remains unclear. Variations in the deiodinase type 1 (DIO1) and type 2 (DIO2) genes that potentially alter thyroid hormone bioactivity may help in elucidating the role of thyroid function in AD.

Objective: We investigated the association of recently identified polymorphisms in the DIO1 (D1a-C/T, D1b-A/G) and DIO2 (D2-ORFa-Gly3Asp, D2-Thr92Ala) genes with circulating thyroid parameters and early neuroimaging markers of AD.

Design and Participants: The Rotterdam Scan Study is a population-based cohort study among 1,077 elderly individuals aged 60–90 yr.

Main Outcome Measures: DIO1 and DIO2 polymorphisms and serum TSH, free T₄, T₃, and reverse T₃ (rT₃) levels were determined in 995 nondemented elderly, including 473 persons with assessments of hippocampal and amygdalar volume on brain magnetic resonance imaging.

Results: Carriers of the D1a-T allele had higher serum free T₄ and rT₃, lower T₃, and lower T₃/rT₃. The D1b-G allele was associated with higher serum T₃ and T₃/rT₃. The DIO2 variants were not associated with serum thyroid parameters. No associations were found with hippocampal or amygdalar volume.

Conclusion: This is the first study to report an association of D1a-C/T and D1b-A/G polymorphisms with iodothyronine levels in the elderly. Polymorphisms in the DIO1 and DIO2 genes are not associated with early magnetic resonance imaging markers of AD. This suggests that the previously reported association between iodothyronine levels and brain atrophy reflects comorbidity or nonthyroidal illness rather than thyroid hormones being involved in developing AD.

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