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Hum. Reprod. Advance Access originally published online on October 14, 2008
Human Reproduction 2009 24(1):241-249; doi:10.1093/humrep/den353
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome

Marlies E. Kevenaar1, Axel P.N. Themmen1, Anke J. van Kerkwijk1, Olivier Valkenburg2, André G. Uitterlinden1,3,4, Frank H. de Jong1, Joop S.E. Laven2 and Jenny A. Visser1,5

1 Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands 2 Department of Obstetrics and Gynaecology, Division of Reproductive Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands 3 Department of Epidemiology and Biostatistics, Erasmus MC, 3000 CA Rotterdam, The Netherlands 4 Department of Clinical Chemistry, Erasmus MC, 3000 CA Rotterdam, The Netherlands

5 Correspondence address. Tel: +31-10-7043346; Fax: +31-10-7035430; E-mail: j.visser{at}erasmusmc.nl

BACKGROUND: Polycystic ovaries display an increased number of pre-antral and antral follicles compared with normal ovaries, suggesting that early and late follicle development are disturbed. The pathophysiology of this process is poorly understood. Since the transforming growth factor β family members, anti-Müllerian hormone (AMH) and bone morphogenetic proteins (BMPs), inhibit FSH sensitivity, their signalling may contribute to the aberrant follicle development in these women. Here, we investigated the role of ALK2, a type I receptor for AMH/BMP signalling, in PCOS using a genetic approach.

METHODS: Seven single nucleotide polymorphisms in the ACVR1 gene, encoding ALK2, were genotyped in 359 PCOS patients and 30 normo-ovulatory and 3543 population-based control women, and haplotypes were determined. Subsequently, the association of ACVR1 variants with ovarian parameters and hormone levels was investigated.

RESULTS: The polymorphisms rs1220134, rs10497189 and rs2033962 and their corresponding haplotypes did not show different frequencies from controls, but were associated with AMH levels in PCOS women (P = 0.001, P = 0.002 and P = 0.007, respectively). Adjustment for follicle number revealed that the association with AMH levels was, in part, independent from follicle number, suggesting that variants in ACVR1 also influence AMH production per follicle.

CONCLUSIONS: Genetic variation within ACVR1 is associated with AMH levels and follicle number in PCOS women, suggesting that ALK2 signalling contributes to the disturbed folliculogenesis in PCOS patients.

Key words: anti-Müllerian hormone/ALK2/polycystic ovary syndrome/folliculogenesis/polymorphism

Submitted on July 18, 2008; resubmitted on August 22, 2008; accepted on September 1, 2008.


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