Genetic studies of pre-eclampsia

Abstract: Pre-eclampsia is a multifactorial, pregnancy-specific vascular disorder characterized by hypertension and proteinuria. It affects around 3-5% of pregnancies worldwide. There is a wide range of phenotypes from mild forms developing in the end of pregnancy, to severe forms with extremely high blood pressure that in worst cases could lead to eclampsia, the occurrence of seizures. Pre-eclampsia and eclampsia account for more than 50 000 maternal deaths per year. The etiology and pathophysiology of preeclampsia remain poorly understood, but it is generally accepted that defect placentation during the early stage of pregnancy, most likely in combination with maternal and environmental factors could lead to systemic inflammation, endothelial dysfunction and the manifestation of the clinical symptoms. Both large epidemiological and family studies have demonstrated genetic contribution to susceptibility. Although several loci have been mapped by linkage analysis only a few promising positional candidate genes have been identified so far. A number of functional candidate genes encoding for coagulation factors, oxidative stress and vasoactive substances, have been suggested to mediate susceptibility, but attempts to replicate these findings have yielded inconsistent results. The overall aim of this thesis was to search for genes predisposing for pre-eclampsia using several different approaches. In Paper I we evaluated the role of the first positionally cloned pre-eclampsia candidate gene STOX1 at 10q22 in the Finnish population. We were unable to validate STOX1 as a common pre-eclampsia gene, and our result is in agreement with two other European studies investigating the same gene. An intriguing association in Paper II suggests that pre-eclampsia share a predisposing genetic factor on chromosome 9p21 with coronary artery disease. To the best of our knowledge we were the first to investigate the role of the 9p21 region in pre-eclampsia. The association of this locus has not been confirmed in other populations and further investigations of the genes in this region are warranted. We have previously mapped a candidate susceptibility locus to chromosome 2p25. In Papers III and IV we present our systematic efforts to narrow down the linkage region by fine-mapping followed by association analysis. In conclusion, our investigations provides an insight into a potential role of a new susceptibility locus for pre-eclampsia at 9p21 in the Finnish population. We were able to narrow down the linkage region at 2p25, but found our sample sets underpowered to evaluate the genes residing within it. Finally, there is no conclusive evidence either for or against STOX1 as a susceptibility gene for pre-eclampsia. To further explore the role of STOX1, much larger sample sets are needed.