LRP5 in premature adrenarche and in metabolic characteristics of prepubertal children

Abstract

Premature adrenarche (PA) is associated with unfavourable metabolic characteristics. We hypothesized that genetic variation in low density lipoprotein (LDL) receptor-related protein 5 (LRP5), which is involved in Wnt signalling in the adrenal cortex and in cholesterol metabolism, plays a role in the pathogenesis of PA. We performed a cross-sectional association study in 73 Finnish children with PA and 97 age- and gender-matched healthy controls. LRP5 genotypes were determined by direct sequencing. Single-marker associations with clinical-metabolic characteristics, including adrenocortical function, glucose tolerance and lipid profile, were examined with age and gender as covariates. Nineteen single nucleotide polymorphisms (SNPs) in LRP5 were found in the 170 children. No significant differences in the genotype distributions were observed between the PA and control groups. SNPs A1330V and N740N were associated with higher serum dehydroepiandrosterone sulphate (DHEAS) levels in the control subjects (A/A vs. A/a; mean 0.8 vs. 1.4 micromol/l, P = 0.01). They were also associated with higher plasma levels of total (4.2 vs. 4.7 mmol/l, P = 0.02) and LDL cholesterol (2.4 vs. 2.9 mmol/l, P = 0.02) in the control group, as was SNP V1119V (P = 0.04 and P = 0.03, respectively). SNPs F549F and V1119V were associated with higher systolic blood pressure (P = 0.04 and P = 0.02, respectively). There were no differences in the parameters of glucose metabolism between the genotype groups. Genetic variation in LRP5 did not predispose to PA but was associated with metabolic characteristics, especially lipid profile, in healthy prepubertal children.