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.

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Keywords ALK2, Anti-Müllerian hormone, Folliculogenesis, Polycystic ovary syndrome, Polymorphism
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Journal Human Reproduction
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Kevenaar, M.E, Themmen, A.P.N, Kerkwijk, A, Valkenburg, O, Uitterlinden, A.G, de Jong, F.H, … Visser, J.A. (2009). Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome. Human Reproduction, 24(1), 241–249. doi:10.1093/humrep/den353