Author:

Keywords:

Adolescent, Aromatase, Base Sequence, Case-Control Studies, Child, DNA, Female, Genetics, Population, Great Britain, Haplotypes, Humans, Hyperandrogenism, Insulin Resistance, Polycystic Ovary Syndrome, Polymorphism, Single Nucleotide, Puberty, Precocious, Spain, Variation (Genetics), Science & Technology, Life Sciences & Biomedicine, Obstetrics & Gynecology, Reproductive Biology, genetic association, insulin resistance, polycystic ovarian syndrome, premature pubarche, testosterone, POLYCYSTIC-OVARY-SYNDROME, SINGLE NUCLEOTIDE POLYMORPHISMS, AROMATASE DEFICIENCY, HYPERGONADOTROPIC HYPOGONADISM, MULTICYSTIC OVARIES, PREMATURE PUBARCHE, POINT MUTATIONS, CANDIDATE GENES, FEMALE, GIRLS, Genetic Variation, United Kingdom, 11 Medical and Health Sciences, 16 Studies in Human Society, Obstetrics & Reproductive Medicine, 3215 Reproductive medicine

Abstract:

BACKGROUND: Aromatase catalyses the conversion of androgens to estrogens and thus variation in the aromatase gene could contribute to female syndromes of androgen excess, such as precocious pubarche (PP) and polycystic ovarian syndrome (PCOS). METHODS: Two groups, one case-control containing girls from Barcelona, Spain with PP (n = 186) or healthy controls (n = 71), and the other a population study of young women from Oxford, UK, who volunteered for a study of normal women's health (n = 109), were genotyped at four aromatase gene haplotype-tag single nucleotide polymorphisms (SNP). Clinical features and hormone concentrations relevant to hyperandrogenism were compared across haplotypes or genotypes. RESULTS: Distributions of aromatase haplotypes (P < / 0.0001) and aromatase SNP_50 genotype (P = 0.001) were significantly different between PP girls and Spanish controls. The AGGG haplotype was associated with an odds ratio (95% confidence interval) of 0.5 (0.3-0.9) (P = 0.005) for the presence of PP compared to GAGG. In 84 post-pubertal PP girls, aromatase haplotype was associated with functional ovarian hyperandrogenism (P < / 0.05), independently of insulin sensitivity. In the Oxford population, SNP_50 was associated with variation in PCOS symptom score (P = 0.008) and circulating testosterone concentrations (P = 0.02). CONCLUSIONS: This study suggests that common variation at the aromatase gene (and not just rare loss-of-function mutations) is associated with androgen excess in girls and young women.