Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism

Biochemical data implicate an underlying disorder of androgen biosynthesisand/or metabolism in the aetiology of polycystic ovary syndrome (PCOS). Wehave examined the segregation of the genes coding for two key enzymes inthe synthesis and metabolism of androgens, cholesterol side chain cleavage(CYP11a) and aromatase (CYP19), with PCOS in 20 multiply-affected families.All analyses excluded CYP19 cosegregation with PCOS, demonstrating thatthis locus is not a major determinant of risk for the syndrome. However,our results provide evidence for linkage to the CYP11a locus (NPL score =3.03, p = 0.003). Parametric analysis using a dominant model suggestsgenetic heterogeneity, generating a maximum HLOD score of 2.7 (alpha =0.63). An association study of 97 consecutively identified Europids withPCOS and matched controls demonstrates significant allelic association of aCYP11a 5' UTR pentanucleotide repeat polymorphism with hirsute PCOSsubjects (p = 0.03). A strong association was also found between alleles ofthis polymorphism and total serum testosterone levels in both affected andunaffected individuals (p = 0.002). Our data demonstrate that variation inCYP11a may play an important role in the aetiology of hyperandrogenaemiawhich is a common characteristic of polycystic ovary syndrome.