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The 23K Variant of the R23K Polymorphism in the Glucocorticoid Receptor Gene Protects against Postnatal Growth Failure and Insulin Resistance after Preterm Birth

Departments of Paediatrics (M.J.J.F., J.M.W.), Clinical Epidemiology (M.J.J.F., F.W.D.), Molecular Epidemiology (I.M., P.E.S.), Clinical Chemistry (M.F.), and Endocrinology and Metabolic Diseases (J.A.R.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: Martijn J. J. Finken, Department of Pediatrics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: m.j.j.finken{at}lumc.nl.

Context: Preterm birth is associated with postnatal growth failure, abdominal fat accumulation, insulin resistance, and hypertension, resembling increased glucocorticoid bioactivity.

Objective: We tested the effects of the R23K and N363S polymorphisms in the glucocorticoid receptor gene, associated with decreased and increased sensitivity to cortisol, respectively, on linear growth and the adult metabolic profile in a cohort (n = 249) of men and women born less than 32 gestational weeks and followed up prospectively from birth until 19 yr of age.

Design and Participants: This was a birth cohort study that included 249 19-yr-old survivors born at a gestational age less than 32 wk from the Dutch Project on Preterm and Small-for-Gestational-Age Infants cohort.

Setting: This project was a nationwide multicenter follow-up study.

Main Outcome Measures: Linear growth and adult body composition, fasting cortisol, glucose, insulin, and cholesterol concentrations, and blood pressure were measured.

Results: The 23K variant (n = 24) was associated with lower fasting insulin levels [mean difference after log transformation: –0.09 (95% confidence interval –0.16, –0.01) mU/liter] and a lower homeostatic model assessment for insulin resistance index [mean difference after log transformation: –0.09 (95% confidence interval –0.16, –0.01)] as well as with a taller stature departing from the age of 1 yr onward. 23K carriers showed complete catch-up growth between the ages of 3 months and 1 yr, and attained height was similar to the population reference mean, whereas stature in noncarriers was on average 0.5 SD below this mean. In contrast, the N363S polymorphism was not associated with any of the outcomes.

Conclusions: Carriers of the 23K variant are, at least in part, protected against postnatal growth failure and insulin resistance after preterm birth.