1. ¹Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
2. ²Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA
3. ³Department of Public Health and General Practice, NTNU, Trondheim, Norway
4. ⁴Department of Perinatal Medicine, Royal Women's Hospital, Melbourne, Australia

Correspondence: LT Roten, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Faculty of Medicine, Kvinne-barn senteret, 1.etg. Øst, Trondheim 7006, Norway. Tel: +47 72573517; Fax: +47 72574704; E-mail: linda.tommerdal@ntnu.no

Received 28 February 2008; Revised 12 June 2008; Accepted 29 July 2008; Published online 10 September 2008.

Abstract

Genome-wide scans in Icelandic, Australian/New Zealand and Finnish pedigrees have provided evidence for maternal susceptibility loci for pre-eclampsia on chromosome 2, although at different positions (Iceland: 2p13 and 2q23, Australia/New Zealand: 2p11–12 and 2q22, Finland: 2p25). In this project, a large population-based (n=65 000) nested case–control study was performed in Norway to further explore the association between positional candidate genes on chromosome 2q and pre-eclampsia, using single-nucleotide polymorphisms (SNPs). DNA samples from 1139 cases (women with one or more pre-eclamptic pregnancies) and 2269 controls (women with normal pregnancies) were genotyped using the Applied Biosystems SNPlex high-throughput genotyping assay. In total, 71 SNPs within positional candidate genes at 2q22–23 locus on chromosome 2 were genotyped in each individual. Genotype data were statistically analysed with the sequential oligogenic linkage analysis routines (SOLAR) computer package. Nominal evidence of association was found for six SNPs (rs1014064, rs17742134, rs1424941, rs2161983, rs3768687 and rs3764955) within the activin receptor type 2 gene (ACVR2A) (all P-values <0.05). The non-independence of statistical tests due to linkage disequilibrium between SNPs at a false discovery rate of 5% identifies our four best SNPs (rs1424941, rs1014064, rs2161983 and rs3768687) to remain statistically significant. The fact that populations with different ancestors (Iceland/Norway–Australia/New Zealand) demonstrate a common maternal pre-eclampsia susceptibility locus on chromosome 2q22–23, may suggest a general role of this locus, and possibly the ACVR2A gene, in pre-eclampsia pathogenesis.