European Journal of Obstetrics & Gynecology and Reproductive Biology
Searching for preeclampsia genes: the current position
Introduction
Eclampsia has been recognized as a pregnancy disorder since antiquity [1], [2]. Since then management and prevention of eclampsia have improved so much that nowadays, in developed countries, it is rarely seen (5 of 10,000 births) and maternal mortality has dropped significantly [3], [4]. Nevertheless, the syndrome of preeclampsia still is one of the major pregnancy disorders and the leading cause of pregnancy-related maternal and fetal morbidity and mortality [5]. Being a pregnancy-related disorder, preeclampsia is believed to have its pathogenic origin at the maternal–fetal interface. Maternal immune maladaptation to the fetal allograft [6], [7], [8], [9], [10], [11] is likely to be involved in its pathogenesis.
Family studies have shown that genetic factors play a role in preeclampsia but the exact inheritance pattern is still unknown [12], [13]. The most plausible genetic model to date postulates that maternal genes dictate a woman’s threshold (susceptibility) for the expression of the preeclampsia phenotype, whereas expression of the phenotype in a woman with a given genetic susceptibility might depend on the genetic load from the trophoblast and possibly environmental factors [9], [14], [15]. Expression of preeclampsia in two equally susceptible women could therefore differ between them depending on their fetal genotype or the environmental circumstances. Although this susceptibility is dictated by genes and their interaction with the environment, it will be transferred into biochemical and molecular changes and hence have systemic influence in the pregnant woman and perhaps in her later life.
Although most molecular genetic studies of preeclampsia to date have focused on maternal susceptibility genes, the direction of future studies is changing towards studying maternal–fetal gene interactions. Given the complexity of preeclampsia on a hemodynamic, biochemical and immunological level, it is not likely that a single maternal gene in combination with a single fetal genotype will reveal its genetic background. So far, finding susceptibility genes for preeclampsia, maternal or fetal, has proven to be difficult. Searching for these genes, however, remains a major challenge since their identification will increase the current insights in the pathophysiology of preeclampsia and facilitate composing genetic risk profiles for preeclampsia in order to prevent or adjust treatment of this common disorder.
Section snippets
Historical background
From Scott and Jenkins’ review on the aetiology of preeclampsia [1], we can learn that Hippocrates noted that drowsiness, fits, and coma were of serious prognostic importance in pregnant women and that Varandaeus in 1619 used the original Greek term ‘eclampsia’ based upon the flashing lights often complained of before a fit in pregnant women. In 1843, Lever reported that eclamptics had albuminuria, and since hypertension and sometimes excessive edema were also present for considerable time
Family studies and postulated inheritance models
A strong familial tendency in preeclampsia has been shown. What model of inheritance fits preeclampsia best has, however, been subject of extensive debate. Still the question whether maternal genes, mainly fetal genes or their interaction predispose for preeclampsia remains unanswered. In Table 1, a chronological overview is given of published family studies, their proposed inheritance model and the hypothesized involvement of maternal or fetal genes or their interaction.
Numerous studies have
Genome-wide scans, linkage studies
The overall result of the candidate gene studies published so far in preeclampsia, as in many other complex disorders, is that they are rarely in accordance with each other. In an attempt to avoid the single-gene approach in candidate gene studies, genome-wide studies for preeclampsia have been initiated. An overview is given in Table 4. In Table 5, levels of significance of lod scores and their P-values used in genome-wide scans according to the guidelines by Lander and Kruglyak [142] are
Future studies, the GOPEC trial
Most candidate studies and all genome-wide scans so far have focused mainly on maternal genetic factors. Since evidence is growing that the fetal gene load influences a mother’s susceptibility to preeclampsia, an interesting large multi-centre trial has recently been initiated in 10 centres across the United Kingdom; the so-called ‘genetics of preeclampsia’ (GOPEC) trial (personal communication). It is a 3-year program of prospective recruitment of 1000 tightly phenotyped mothers with
Discussion/conclusion
Although the search for ‘the preeclampsia gene’ has been—and still is—extensive, no one has found ‘the’ gene yet. The most convincing result so far has been the chromosome 2p13 locus in the genome-wide scan of Arngrı́msson et al. [108]. However, contribution to the 2p13 locus came mainly from two large families comprising only 17 (5%) of the total of 343 affected individuals in the Icelandic study population. These 17 individuals represented 2% of the mildly affected women and 7.5% of the
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