Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome.
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 beta 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.
Kevenaar
Marlies E
ME
Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Themmen
Axel P N
AP
van Kerkwijk
Anke J
AJ
Valkenburg
Olivier
O
Uitterlinden
André G
AG
de Jong
Frank H
FH
Laven
Joop S E
JS
Visser
Jenny A
JA
D030201:Activin Receptors, Type I / Q000235:genetics* / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054304:Anti-Mullerian Hormone / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D006080:Ovarian Follicle / Q000378:metabolism / Q000502:physiology; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015398:Signal Transduction
D054304:Anti-Mullerian Hormone; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I