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Androgen Receptor Gene CAG Repeat Polymorphism and X-Chromosome Inactivation in Children with Premature Adrenarche

Department of Pediatrics, Kuopio University and University Hospital, 70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Saila Lappalainen, M.D., Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio, Finland. E-mail: saila.lappalainen{at}uku.fi.

Context: There is variation in the adrenal androgen levels and clinical findings of children with premature adrenarche (PA).

Objectives: We hypothesized that androgen sensitivity, indicated by the length of CAG repeat in the X-chromosomal androgen receptor (AR) gene has a role in the polygenic pathogenesis of PA.

Design and Patients: We performed a cross-sectional association study among 73 Finnish Caucasian children with PA (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls).

Main Outcome Measures: AR gene methylation-weighted CAG_n(mwCAG_n) via CAG_n length and X-chromosome inactivation analysis and clinical phenotype were determined.

Setting: The study took place at a university hospital.

Results: PA subjects had significantly shorter mwCAG_n than controls [mean difference (95% confidence interval); 0.76 (0.14–1.38); P = 0.017]. AR gene mwCAG_n did not correlate with androgen or SHBG levels in either group. In children with PA, mwCAG_n correlated positively with body mass index (BMI) ( = 0.19; P = 0.02). The mean of mwCAG_n was significantly shorter in PA children with lower BMI compared with PA children with higher BMI [BMI SD score < 0.79, n = 35, vs. BMI SD score > 0.79, n = 36; 1.13 (0.38–1.87), P = 0.004] and in PA children with lower BMI compared with healthy children with same BMI (P = 0.004).

Conclusions: The AR gene CAG_n polymorphism may have a significant role in the pathogenesis of PA, especially in lean children.