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UNRAVELLING THE GENETIC BASIS OF PRE-ECLAMPSIA
Brennecke S P
Department of Perinatal Medicine, Royal Women’s Hospital
and
Department of Obstetrics and Gynaecology, University of Melbourne
Melbourne
Australia
Pre-eclampsia is a common and serious medical disorder of human pregnancy. It is associated
with substantial maternal and perinatal morbidity and mortality throughout the world.
The clinical diagnosis of pre-eclampsia is based primarily on the detection of new-onset
hypertension and proteinuria, usually occurring during the latter half of pregnancy.
The pathogenesis of pre-eclampsia is complex and incompletely understood. However,
deficient placentation is widely accepted to be a critical lesion in the aetiology of this disorder.
As well, pre-eclampsia has a significant heritable component, with recent estimates of
heritability greater than 0.5 being reported in several populations. While a familial susceptibility
to pre-eclampsia has been recognised for many years, the mode of inheritance remains a topic
of debate. Increasingly, there is consensus that mother and fetus both contribute to the genetic
risk for pre-eclampsia, with the fetal contribution reflecting the influence of paternal genes. This
degree of complexity confounds any simple Mendelian monogenic pattern of inheritance for preeclampsia susceptibility. Instead, it is likely to involve multiple genetic and environmental
contributions, together with their interactions. Clarification of the genetic basis of pre-eclampsia
would represent a major step forward in our understanding of this disease and facilitate the
development of novel and specific prophylactic and therapeutic interventions.
To this end, and as with other common complex human genetic traits, several research groups
have pursued a positional cloning strategy in attempts to identify susceptibility loci for preeclampsia. Genome-wide scans which have been performed on pre-eclampsia-affected
families include studies on populations from Iceland (Arngrimsson et al 1999), Australia and
New Zealand (Moses et al 2000), The Netherlands (Lachmeijer et al 2001), and Finland
(Laivuori et al 2002). Three of these studies provided evidence of susceptibility loci on
chromosome 2, albeit at different positions.
However, a recognised limitation in most genome-wide scans is the low precision of
susceptibility gene localisation.
Map location estimation errors, genotyping errors and
phenotype misclassification can all limit the reliability of estimating the chromosomal location of
a disease locus (Gőring and Terwilliger 2000). To improve the precision of susceptibility gene
localisation, fine mapping strategies involving saturation of the candidate region with additional
genetic markers (e.g. single nuclear type polymorphisms) with simultaneous exploitation of
information on both linkage and linkage disequilibrium can be helpful. This approach has
yielded strong support for the location of a pre-eclampsia susceptibility gene on chromosome 2
(Fitzpatrick et al 2004).
Having identified and fine mapped a linkage region on chromosome 2, several hundred
positional candidate genes in the region still require detailed study to identify the key genetic
lesion responsible for pre-eclampsia susceptibility. Candidates with functional implications for
placental development are obviously of interest in this regard.
Contemporary genomic techniques promise to provide further definitive insights into the precise
genetic basis of pre-eclampsia. Such techniques include variance component-based linkage
approaches, together with objective prioritization of the positional candidate genes using a
combination of bioinformatics and assessment of differential gene expression in decidual tissue
from pre-eclampsia and normotensive women.
References:
Arngrimsson R, Sigurardottir S, Frigge ML, Bjarnadttir RL, Jonsson T, Stefansson H,
Baldursdottir A, Einarsdottir AS, Palsson B, Snorradottir S, Lachmeijer AM, Nicolae D, Kong A,
Bragason BT, Gulcher JR, Geirsson RT, Stefansson K. A genome-wide scan reveals a
maternal susceptibility locus for preeclampsia on chromosome 2p13. Human Mol Genet 1999;
8(9): 1799-1805
Fitzpatrick G, Gőring HH, Liu H, Borg A, Forest S, Cooper DW, Brennecke SP, Moses EK.
Fine mapping and SNP anaysis of positional candidates at the preeclampsia susceptibility locus
(PREG1) on chromosome 2. Human Biol 2004; 76(6): 849-862.
Gőring HH, Terwilliger JD. Linkage analysis in the presence of errors III: Marker loci and their
map as nuisance parameters. Am J Hum Genet 2000; 66(4): 1298-1309.
Lachmeijer AM, Arngrimsson R, Bastiaans EJ, Frigge ML, Pals G, Sigurdardottir S, Stefansson
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Laivouri H, Lahermo P, Ollikainen V, Widen E, Haiva-Mallinen L, Sundstrom H, Laitinen T,
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9p13 in Finnish families. Am J Hum Genet 2003; 72(1): 168-177.
Moses EK, Lade JA, Guo G, Wilton AN, Grehan M, Freed K, Borg A, Terwilliger JD, North R,
Cooper DW, Brennecke SP. A genome scan in families from Australia and New Zealand
confirms the presence of a maternal susceptibility locus for preeclampsia, on chromosome 2.
Am J Hum Genet 2000; 67(6): 1581-1585.