Genetics of polycystic ovary syndrome

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Abstract

We have found evidence for the involvement of two major genes in the aetiology of PCOS. The results of both linkage and association studies suggest that CYP11a (coding for P450 cholesterol side chain cleavage) and the insulin VNTR regulatory polymorphism are important genes in the aetiology of PCOS and may explain, in part, the heterogeneity of the syndrome. Differences in expression of CYP11a could account for variation in androgen production in women who have polycystic ovaries and those subjects who are homozygous for III alleles at the insulin gene VNTR locus are more likely to be hyperinsulinaemic. It is likely that other genes are involved in the aetiology of PCOS. Recent results lend weight to the idea that PCOS represents a complex trait in which several genes—but perhaps a relatively small number of key genes—contribute, in conjunction with nutritional factors, to the observed clinical and biochemical heterogeneity.

Introduction

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility and hirsutism (Adams et al., 1986, Hull et al., 1987). Polycystic ovary syndrome has been defined as the association of menstrual disturbance with clinical or biochemical evidence of androgen excess (Zawadzki et al., 1992), however, the validity of this definition is questionable (Conway et al., 1989, Franks et al., 1989, Franks et al., 1995). Using ultrasonographic criteria, the majority of hirsute women with regular menses have been found to have polycystic ovaries (Franks et al., 1989, O’Driscoll et al., 1994) and the estimated prevalence of the polycystic ovaries in a normal (volunteer) population has been found to be over 20% (Polson et al., 1988, Clayton et al., 1992).

It has been suggested that PCOS represents a wide range of disorders rather than a single entity but certain biochemical features are common to all groups of subjects with ultrasonographic evidence of polycystic ovaries irrespective of the clinical presentation. Hyperandrogenism is the most consistent endocrine feature in women with polycystic ovaries, whether the mode of presentation is as the ‘classic’ syndrome or as an incidental finding on ultrasound examination (Franks et al., 1991). The ovary, rather than the adrenal, is the major source of excess androgen (Franks et al., 1995) and recent data from both clinical investigations and studies of isolated human theca cells implicate a primary ovarian abnormality rather than a ‘downstream’ effect of elevated serum luteinsing hormone levels (Gilling-Smith et al., 1994, Gilling-Smith et al., 1997, Ibanez et al., 1996).

Polycystic ovary syndrome is also characterised by significant metabolic abnormalities which include fasting and glucose-stimulated hyperinsulinaemia, peripheral insulin resistance, abnormalities of energy expenditure and dyslipidaemia (Franks et al., 1995, Dunaif et al., 1997, Holte et al., 1996). PCOS represents a major risk factor for development of NIDDM (Dunaif et al., 1997, Holte et al., 1996, Dunaif et al., 1987, Dunaif et al., 1996). The prevalence of NIDDM in a long-term follow-up study of postmenopausal women with a previous history of PCOS was found to be 13% compared with <2% in the reference population (Dahlgren et al., 1956). These patients may also be at greater risk of developing cardiovascular disease in the future (Dahlgren et al., 1992).

Familial clustering of cases suggests a major genetic component to the aetiology of PCOS. Although it seems unlikely that there is a single cause of the syndrome, our hypothesis is that much of the clinical and biochemical variability within PCOS can be explained by the interaction of environmental (notably nutritional) factors with a small number of major causative genes which include those involved in androgen production and the secretion and/or action of insulin.

Genetic studies of polycystic ovary syndrome are difficult to perform (Simpson et al., 1992, Legro et al., 1995). The heterogeneity and the lack of universally acceptable clinical or biochemical diagnostic criteria have been discussed. Another major problem is that this is a disorder which primarily affects women of reproductive age and it is therefore very difficult for segregation studies to span more than one generation. In addition, as discussed below, there is no commonly accepted male phenotype. Finally, the high prevalence of polycystic ovaries in the population means that large pedigrees, in particular, may include subjects with polycystic ovaries arising from a different genotype from that of the proband. Nevertheless, given modern methods of genetic modelling and molecular genotyoping, these problems can be overcome.

Section snippets

Familial polycystic ovary syndrome

Familial aggregation of cases of polycystic ovary syndrome is well recognised (Simpson et al., 1992, Legro et al., 1995, Cooper et al., 1968, Ferriman et al., 1979, Hague et al., 1988, Givens, 1988, Lunde et al., 1989, Carey et al., 1993). Not surprisingly, the criteria used to identify probands and affected family members vary considerably between studies. Furthermore, identification of affected family members was made by direct clinical observation in some studies, by questionnaires alone in

The 17 hydroxylase/17, 20 lyase gene (CYP17)

Our initial investigations concentrated on CYP17 (the gene encoding P450c17a) because clinical studies pointed to abnormal regulation of 17-hydroxylase/17,20-lyase (a known rate-limiting step in androgen biosynthesis) (Barnes et al., 1989, Rosenfield et al., 1990). A 459bp fragment in the 5′ untranslated region of CYP17 was amplified by a polymerase chain reaction (PCR). A common variant form was identified which was characterised by a T to C substitution at −34 base pairs from the start point

Acknowledgements

We thank Dr A.H. Carey, Dr C.M.-T. Gilling-Smith, R. Joseph-Horne (St Mary’s Hospital, London), Dr G.S. Conway (The Middlesex Hospital, London), S. Hague (Department of Biochemistry and Molecular Genetics, Imperial College School of Medicine at St Mary’s, London), Dr S.T. Bennett, Professor J.A. Todd (Wellcome Trust Centre for Human Genetics, University of Oxford) for their invaluable contributions to these studies. We are very grateful for grant support from The Medical Research Council

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    1

    Current address: Centre for Genetics of Cardiovascular Disorders, Department of Medicine, University College London Medical School, London WC1E 6JJ, UK.

    2

    Current address: Murdoch Institute, Royal Children’s Hospital, Parkville, Melbourne, Australia.

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