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Large-Scale Analysis of the Relationship between CYP11A Promoter Variation, Polycystic Ovarian Syndrome, and Serum Testosterone

Genomic Medicine, Faculty of Medicine (M.G., L.H., N.G., A.B., S.H., M.I.M.) and Institute of Reproductive and Developmental Biology (M.G., S.F.), Imperial College, Hammersmith Campus, London W12 0NN, United Kingdom; Departments of Epidemiology and Public Health (U.S., M.-R.J.) and Reproductive Endocrinology (K.R., M.J.G., S.F.), Imperial College, St. Mary’s Campus, London W2 1PG, United Kingdom; Wellcome Trust Centre for Human Genetics (B.L.P., C.J.G., M.I.M.) and Oxford Centre for Diabetes, Endocrinology and Metabolism (B.L.P., A.B., C.J.G., M.I.M.), Churchill Hospital, Oxford OX3 7LJ, United Kingdom; Department of Obstetrics and Gynaecology (G.S.C.), Bloomsbury Site, University College, London WC1E 6BT, United Kingdom; and Departments of Clinical Chemistry (A.R., S.T.), Obstetrics and Gynecology (S.T., H.M., A.-L.H.), and Public Health Science and General Practice (M.-R.J., S.T., A.P.), University of Oulu, Oulu, Finland 90014

Address all correspondence and requests for reprints to: Prof. Mark McCarthy, Robert Turner Professor of Diabetes, Oxford Centre for Diabetes, Endocrinology & Metabolism, Churchill Hospital Site, Old Road, Headington, Oxford OX3 7LJ, United Kingdom. E-mail: Mark.mccarthy{at}drl.ox.ac.uk.

CYP11A, the gene encoding P450scc, a key enzyme in steroid biosynthesis, is a strong biological candidate for polycystic ovary syndrome (PCOS) susceptibility. Four of the five published studies that have examined CYP11A for evidence of linkage and/or association have reported significant relationships with polycystic ovary (PCO) status and/or serum testosterone levels. However, study sizes have been modest, and the current study aimed to reevaluate these findings using significantly larger clinical resources. A pair of CYP11A promoter microsatellites, including the pentanucleotide (D15S520) previously implicated in trait susceptibility, were genotyped in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1589 women from a population-based birth cohort from Finland characterized for PCO symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study (for example, an excess of the pentanucleotide four-repeat allele in cases, P = 0.005), these findings were not substantiated in the other analyses, and no discernable relationship was seen between variation at these loci and serum testosterone levels. These studies indicate that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes has been substantially overestimated in previous studies.

This work was supported by the United Kingdom Medical Research Council (Program Grant G9700120), the Academy of Finland, the European Commission (Framework 5 Award QLG1-CT-2000-01643), and the Wellcome Trust (Project Grant GR069224MA).

Abbreviations: PCO, Polycystic ovary; PCOS, PCO syndrome; USS, ultrasound scan.

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