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Mol. Hum. Reprod. Advance Access originally published online on January 6, 2009
Molecular Human Reproduction 2009 15(3):195-204; doi:10.1093/molehr/gap001
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© The Author 2009. 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

Genetic association of the activin A receptor gene (ACVR2A) and pre-eclampsia

E. Fitzpatrick1,5, M.P. Johnson2, T.D. Dyer2, S. Forrest3, K. Elliott4,6, J. Blangero2, S.P. Brennecke1 and E.K. Moses2,7

1Department of Perinatal Medicine and University of Melbourne Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Parkville, VIC 3052, Australia 2Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78227, USA 3Australian Genome Research Facility Ltd, Parkville, VIC 3052, Australia 4ChemGenex Pharmaceuticals, Geelong, VIC 3216, Australia

7 Correspondence address. E-mail: moses{at}sfbrgenetics.org

Pre-eclampsia is a common serious disorder of human pregnancy, which is associated with significant maternal and perinatal morbidity and mortality. The suspected aetiology of pre-eclampsia is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. Recently, we reported significant linkage to chromosome 2q22 in 34 Australian/New Zealand (Aust/NZ) pre-eclampsia/eclampsia families, and activin A receptor type IIA (ACVR2A) was identified as a strong positional candidate gene at this locus. In an attempt to identify the putative risk variants, we have now comprehensively re-sequenced the entire coding region of the ACVR2A gene and the conserved non-coding sequences in a subset of 16 individuals from these families. We identified 45 single nucleotide polymorphisms (SNPs), with 9 being novel. These SNPs were genotyped in our total family sample of 480 individuals from 74 Aust/NZ pre-eclampsia families (including the original 34 genome-scanned families). Our best associations between ACVR2A polymorphisms and pre-eclampsia were for rs10497025 (P = 0.025), rs13430086 (P = 0.010) and three novel SNPs: LF004, LF013 and LF020 (all with P = 0.018). After correction for multiple hypothesis testing, none of these associations reached significance (P > 0.05). Based on these data, it remains unclear what role, if any, ACVR2A polymorphisms play in pre-eclampsia risk, at least in these Australian families. However, it would be premature to rule out this gene as significant associations between ACVR2A SNPs and pre-eclampsia have recently been reported in a large Norwegian (HUNT) population sample.

Key words: activin/ACVR2A/genetic association/pre-eclampsia/SNP

5 Present address: Genetic Health Research (Bruce Lefroy Centre), Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia.

6 Present address: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.

Submitted on November 18, 2008; resubmitted on December 24, 2008; accepted on December 31, 2008.


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