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A Polymorphism in Type I Deiodinase Is Associated with Circulating Free Insulin-Like Growth Factor I Levels and Body Composition in Humans

Departments of Internal Medicine (R.P.P., A.W.v.d.B., H.v.T., A.G.U., J.A.M.J.L.J., S.W.J.L., T.J.V.), Clinical Chemistry (A.G.U.), and Epidemiology and Biostatistics (A.G.U.), Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Robin P. Peeters, M.D., Department of Internal Medicine, Room Ee 502, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: r.peeters{at}erasmusmc.nl.

The interaction between the GH-IGF-I axis and thyroid hormone metabolism is complex and not fully understood. T₄ stimulates IGF-I activity in animals in the absence of GH. On the other hand, GH replacement therapy results in an increase in serum T₃ and a decrease in T₄ and rT₃ levels, suggesting a stimulation of type I deiodinase (D1) activity. Recently, we demonstrated the association of two polymorphisms in D1 (D1a-C/T; T = 34%, and D1b-A/G; G = 10%) with serum iodothyronine levels. Haplotype alleles were constructed, suggesting a lower activity of the D1 haplotype 2 allele (aT-bA) and a higher activity of the haplotype allele 3 (aC-bG). In this study, we investigated whether genetic variations in D1 are associated with the IGF-I system.

In 156 blood donors and 350 elderly men, the association of the D1 haplotype alleles with circulating IGF-I and free IGF-I levels was studied. In addition, potential associations with muscle strength and body composition were investigated in the elderly population. Finally, the relation between serum iodothyronine levels and IGF-I levels was studied.

In blood donors, haplotype allele 2 was associated with higher levels of free IGF-I (302.9 ± 22.9 vs. 376.3 ± 19.1 pg/ml, P = 0.02). In elderly men, haplotype allele 2 also showed an allele dose increase in free IGF-I levels (P_trend = 0.01) and an allele dose decrease in serum T₃ levels (P_trend = 0.01), independent of age. Carriers of the D1a-T variant also had a higher isometric grip strength (P = 0.047) and maximum leg extensor strength (P = 0.07) as well as a higher lean body mass (P = 0.03).

In blood donors, T₄ and free T₄ were negatively correlated with total IGF-I levels (R = –0.18, P = 0.03 and R = –0.24, P = 0.003), whereas T₃ to T₄ and T₃ to reverse T₃ ratios were positively correlated with total IGF-I (R = 0.31, P < 0.001 and R = 0.18, P = 0.03). Free IGF-I showed a negative correlation with T₄ (R = –0.26, P = 0.001) and T₄-binding globulin (R = –0.31, P < 0.001) and a positive correlation with T₃ to T₄ ratio (R = 0.21, P = 0.01).

In conclusion, a polymorphism that results in a decreased D1 activity is associated with an increase in free IGF-I levels. The pathophysiological significance of this association with IGF-I is supported by an increased muscle strength and muscle mass in carriers of the D1 haplotype 2 allele in a population of elderly men. The association of D1 haplotype allele 2 with serum T₃ levels in the elderly population suggests a relative increase in its contribution to circulating T₃ in old age.

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