414. The role of low-frequency variants in pre-eclampsia: Recent findings in a Finnish population

Abstract

The genetic basis of pre-eclampsia and its link with increased lifetime risk of cardiovascular diseases in women with a history of pre-eclampsia and children born from pre-eclamptic pregnancies are incompletely understood. Genetic factors have been shown to account for 55% of the liability of pre-eclampsia with 35% attributed to the maternal genetic effects and 20% to the fetal genetic effects (Cnattingius et al. Am J Med Genet 2004). Genome-wide association screening in offspring from pre-eclamptic pregnancies performed by a collaboration between research groups has already proven a successful approach in finding a common sequence variant near the fms related tyrosine kinase gene (FLT1) associated with pre-eclampsia (McGinnis et al. Nat Genet 2017). The sequencing approach enables identification of both common and rare variants, but is challenging in common complex disorders like pre-eclampsia. An isolated population may offer a major advantage for genetic discovery. In Finland a strong founding bottleneck has been shown to cause enrichment of some low-frequency variants (Lim et al. PLOS Genet 2014). Centrally collected registers with lifelong medical histories can be used together with genetic data to better understand diseases associated with pre-eclampsia. We designed a targeted sequencing study to screen the coding and splicing areas of genes of interest in pre-eclampsia and found maternal low-frequency variants in FLT1 which may protect from pre-eclampsia (Lokki et al. Hypertension 2017). Using data from health registers we found that the same variants may also protect from heart failure later in life. Future studies are needed to improve our understanding of the genetic background pre-eclampsia and its links to other diseases. Any new gene discovery will highlight a known pathway or reveal a new biochemical pathway in the pathogenic process leading to pre-eclampsia and may also help in prediction and in identifying individuals with higher risk for later cardiovascular disease.