ASSOCIATION OF THE STEROID-SYNTHESIS GENE CYP11A WITH POLYCYSTIC-OVARY-SYNDROME AND HYPERANDROGENISM

Biochemical data implicate an underlying disorder of androgen biosynth esis and/or metabolism in the aetiology of polycystic ovary syndrome ( PCOS), We have examined the segregation of the genes coding for two ke y enzymes in the synthesis and metabolism of androgens, cholesterol si de chain cleavage (CYP11a) and aromatase (CYP19), with PCOS in 20 mult iply-affected families, All analyses excluded CYP19 co-segregation wit h PCOS, demonstrating that this locus is not a major determinant of ri sk for the syndrome, However, our results provide evidence for linkage to the CYP11a locus (NPL score = 3.03, p = 0.003), Parametric analysi s using a dominant model suggests genetic heterogeneity, generating a maximum HLOD score of 2.7 (alpha = 0.63), An association study of 97 c onsecutively identified Europids with PCOS and matched controls demons trates significant allelic association of a CYP11a 5' UTR pentanucleot ide repeat polymorphism with hirsute PCOS subjects (p = 0.03), A stron g association was also found between alleles of this polymorphism and total serum testosterone levels in both affected and unaffected indivi duals (p = 0.002), Our data demonstrate that variation in CYP11a may p lay an important role in the aetiology of hyperandrogenaemia which is a common characteristic of polycystic ovary syndrome.