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AN OBJECTIVE PRIORITISATION STRATEGY FOR THE DETECTION AND ANALYSIS OF
CANDIDATE GENES AT THE PRE-ECLAMPSIA SUSCEPTIBILITY LOCUS, PREG1, ON
CHROMOSOME 2.
Fitzpatrick E 1,2, Blangero J 3, Forrest S 4, Cooper DW 5, Brennecke SP 1,2, Moses EK 3.
1
Department of Perinatal Medicine, The Royal Women's Hospital, Carlton, Victoria, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Carlton, Victoria,
Australia.
3
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio,
Texas, USA.
4
Australian Genome Research Facility, Walter and Eliza Hall Institute, Parkville, Victoria,
Australia.
5
School of Biological Sciences, Macquarie University, North Ryde, New South Wales,
Australia.
2
Introduction: Pre-eclampsia/eclampsia (PE/E) is one of the most dangerous complications of human
pregnancy. While it is clear that heritable factors play a major role in susceptibility to PE the genetics
are complex and poorly understood. During the past few years, enormous advances have been made
in techniques for finding and identifying genetic loci that influence complex human disease related
traits. Previously, we carried out a genome wide scan of Australian and New Zealand PE families that
revealed a putative susceptibility locus spanning a broad region on chromosome 2. This region,
designated PREG1 (PRe-eclampsia/Eclampsia Gene 1), contains over 300 genes. The choice now
lies between sequencing large numbers of genes, or setting priorities by combining positional data
with functional and expression data. We have applied an objective prioritisation strategy that combines
novel bioinformatics, gene expression profiling and SNP association analysis.
Aim: To identify maternal susceptibility genes for PE/E at the chromosome 2 locus, PREG1.
Methods: To prioritise positional candidate genes within the PREG1 locus for detailed analysis, we
have applied an objective prioritisation strategy that integrates novel bioinformatic database search
tools, assessment of differential gene expression using targeted microarray analysis of decidual
tissues and single nucleotide polymorphism (SNP) association analysis.
Results: Our bioinformatics tool assigned the highest priority to the activin receptor gene ACVR2. This
gene also showed greater than 10-fold differential gene expression in decidual tissues from
normotensive versus PE individuals. Of five known SNPs from this gene that were genotyped in our
cohort one SNP (rs1424954) showed strong preliminary evidence of association with PE (p = 0.007).
Haplotype analysis revealed no additional association information suggesting that the observed signal
may be the signature of the functional variant.
Conclusions: By taking an integrative approach that combines traditional linkage methodologies with
bioinformatics and gene expression analyses we have identified a novel putative PE maternal
susceptibility gene showing genetic association and altered gene expression in PE patients.