Candidate gene analysis in premature pubarche and adolescent hyperandrogenism

Objective: To identify genetic markers associated with premature pubarche in children and hyperandrogenism in adolescent girls. Design: Association study. Setting: Academic research environment. Patient(s): Forty children with premature pubarche (PP), 29 adolescent girls with hyperandrogenism (HA), and 15 healthy control women. Intervention(s): None. Main Outcome Measure(s): Genetic variations at five loci selected because of known associations with hyperandrogenism, insulin resistance, hyperinsulinemia, or obesity. Result(s): Heterozygosity for CYP21 mutations was identified in 14 of 40 (35%) PP, 8 of 29 (28%) HA, and 1 of 30 (3%) controls. Heterozygosity for HSD3B2 variants was identified in 3 of 40 (7.5%) PP, 5 of 29 (17%) HA, and 0/15 controls. Among the PP, 11 of 80 (14%), 5 of 80 (6%), and 7 of 80 (9%) alleles showed the IRS-1 , GRL , and ADRB3 variants, respectively. Among the HA, 5 of 58 (8.6%), 3 of 58 (5%), and 6 of 58 (10%) alleles showed the IRS-1 , GRL , and ADRB3 variants, respectively. Among the control participants, variant allele frequency was 1 of 30 (3.3%) for IRS-1 , 2 of 30 (6.6%) for GRL , and 2 of 30 (6.6%) for ADRB3 . Conclusion(s): Our findings suggest that the development of PP and HA can be associated with the occurrence of multiple sequence variants at five susceptibility loci, especially steroidogenic enzyme genes. This approach offers a novel paradigm to investigate and identify the genetic factors relevant to polycystic ovary syndrome.