Protective Low-Frequency Variants for Preeclampsia in the Fms Related Tyrosine Kinase 1 Gene in the Finnish Population

A Inkeri Lokki, Emma Daly, Michael Triebwasser, Mitja I Kurki, Elisha D O Roberson, Paavo Häppölä, Kirsi Auro, Markus Perola, Seppo Heinonen, Eero Kajantie, Juha Kere, Katja Kivinen, Anneli Pouta, Jane E Salmon, Seppo Meri, Mark Daly, John P Atkinson, Hannele Laivuori

Research output: Contribution to journalArticleScientificpeer-review

19 Citations (Scopus)

Abstract

Preeclampsia is a common pregnancy-specific vascular disorder characterized by new-onset hypertension and proteinuria during the second half of pregnancy. Predisposition to preeclampsia is in part heritable. It is associated with an increased risk of cardiovascular disease later in life. We have sequenced 124 candidate genes implicated in preeclampsia to pinpoint genetic variants contributing to predisposition to or protection from preeclampsia. First, targeted exomic sequencing was performed in 500 preeclamptic women and 190 controls from the FINNPEC cohort (Finnish Genetics of Preeclampsia Consortium). Then 122 women with a history of preeclampsia and 1905 parous women with no such history from the National FINRISK Study (a large Finnish population survey on risk factors of chronic, noncommunicable diseases) were included in the analyses. We tested 146 rare and low-frequency variants and found an excess (observed 13 versus expected 7.3) nominally associated with preeclampsia (P<0.05). The most significantly associated sequence variants were protective variants rs35832528 (E982A; P=2.49E-4; odds ratio=0.387) and rs141440705 (R54S; P=0.003; odds ratio=0.442) in Fms related tyrosine kinase 1. These variants are enriched in the Finnish population with minor allele frequencies 0.026 and 0.017, respectively. They may also be associated with a lower risk of heart failure in 11 257 FINRISK women. This study provides the first evidence of maternal protective genetic variants in preeclampsia.

Original languageEnglish
Pages (from-to)365-371
Number of pages7
JournalHypertension
Volume70
Issue number2
DOIs
Publication statusPublished - Aug 2017
Externally publishedYes
Publication typeA1 Journal article-refereed

Keywords

  • Adult
  • Female
  • Finland/epidemiology
  • Genetic Variation
  • Humans
  • Hypertension/diagnosis
  • Pre-Eclampsia/epidemiology
  • Pregnancy
  • Protective Factors
  • Vascular Endothelial Growth Factor Receptor-1/genetics

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