Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17

Abstract

Fourteen Caucasian families with 81 affected individuals have been assessed in which polycystic ovaries/male pattern baldness (PCO/MPB) segregates as an autosomal dominant phenotype (1). The gene CYP17, coding for P450c17 alpha (17 alpha-hydroxylase; 17/20 lyase) on chromosome 10q24.3 is the rate-limiting step in androgen biosynthesis. We have identified a new single base change in the 5' promoter region of CYP17 by heteroduplex analysis. This creates an additional SP1-type (CCACC box) promoter site, which may cause increased expression. This base change also creates a recognition site for the restriction enzyme MspA1 allowing a simple screening procedure. There is a significant association between the presence of this base change (A2) and the affected state for consecutively identified Caucasian women with PCO as compared either to consecutively matched controls (P = 0.03) with an odds ratio for those with at least one A2 allele of 3.57, or to a random population (P = 0.02) with an odds ratio of 2.50. Within the fourteen families, members with PCO or MPB have a significant association with the occurrence of at least one A2 allele compared to their normal relatives, with an odds ratio of 2.20 (P = 0.05). The base change does not cosegregate with the affected phenotype within the families showing association, demonstrating that this mutation of CYP17 does not cause PCO/MPB. Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect.

Studying the genetic predisposing factors in the pathogenesis of acne vulgaris

“…The role of the Ϫ34TϾC promoter polymorphism has been investigated in various types of endocrinopathies and cancers too, and positive associations have been reported between this SNP and premature baldness, polycystic ovary syndrome [89], and breast cancer [90]. In prostate cancer various findings have been reported [91], and the association with this disease has therefore not been proven beyond doubt.…”

“…It is suggested that the polymorphism may affect the regulation of the CYP17 gene by creating a novel SP1 promoter-binding site [89], although in vitro EMSA experiments have so far not furnished physical evidence of the SP1 binding of this putative "novel" site [93]. However, the fact that several studies have indicated an association between the SNP and different endocrinopathies suggests that the role of this polymorphism is currently controversial, and establishment of its exact molecular function requires further investigations.…”

Variants in hormone biosynthesis genes and risk of endometrial cancer

“…The study by Gaudet et al [23] found, as we did, no difference in results according to levels of BMI, while Haiman et al [24] found a stronger effect in obese women. The C allele was originally thought to be associated with an Sp-1 binding site that would lead to higher expression [25]; however, a later study did not support this [26]. Several studies have examined the relationship between CYP17A1 genotype and serum levels of androgens, estrogens, or progesterone.…”

Polycystic Ovary Syndrome in Adolescence

“…Only half of these sisters, however, had symptoms such as menstrual irregularity. Polycystic ovaries appear to occur as a dominant trait, with a suggestion of a counterpart male phenotype of premature male-pattern baldness [44,45]. Polycystic ovaries from asymptomatic women have an abnormal steroidogenic pattern similar to that of women with PCOS in vitro [46], and ovarian function testing shows them to have a subclinical increase in androgens [47][48][49].…”