title: OS077. The chromosome 2q22 preeclampsia susceptibility locus reveals shared novel risk factors for CVD.
abstract: BACKGROUND
  We have previously localized a preeclampsia susceptibility locus on chromosome 2q22 in 34 Australian and New Zealand (AUS/NZL) families. Using an extended number of AUS/NZL families (n=74) we have now performed a comprehensive molecular genetics dissection of this locus.
  
  
  OBJECTIVE
  Identify causal genetic risk factors for preeclampsia at the 2q22 risk locus.
  
  
  METHODS
  To prioritize positional candidate genes for analysis we used a combination of bioinformatics, SNPing, whole-genome transcriptional profiling and proximity to the peak linkage signal. Prioritized genes were earmarked for exon-centric re-sequencing in 48 founder individuals from the 74 AUS/NZL families. All identified sequence variants were genotyped back in this extended familial cohort. Variants showing the strongest genetic association were genotyped in independent case-control cohorts from Australia (n=1095), Norway (n=3397) and Finland (n=1519), and in a large cohort of Mexican American families rich in quantitative cardiovascular disease (CVD) risk traits.
  
  
  RESULTS
  We interrogated 1598 variants from 52 genes and identified four independent SNPs to be significantly associated with preeclampsia susceptibility in the 74 AUS/NZL families. These four SNPs reside in four novel preeclampsia candidate genes: LCT (rs2322659, p=0.002), LRP1B (rs35821928, p=0.0001), RND3 (rs115015150, p=0.002) and GCA (rs17783344, p=0.002). We could only replicate the LCT SNP association in the Australian case-control population (p=0.04, combined p=0.001). These four SNPs are however, significantly associated with several quantitative CVD risk traits such as oxidative stress indicators, inflammatory biomarkers and obesity risk factors.
  
  
  CONCLUSIONS
  Previous independent studies have reported significant genetic associations with total cholesterol levels and obesity risk factors for variants within LCT and LRP1B, respectively. RND3 inhibits the biological activity of a downstream effector protein, ROCK, which is known to affect endothelial dysfunction, inflammation, oxidative stress and vascular re-modeling. Grancalcin (GCA) is known to impact the adhesive properties of fibronectin, a marker for endothelial vascular injury. To our knowledge, data from the current study present for the first time empirical evidence of possible shared genetic risk factors underlying both preeclampsia and other CVD-related traits.
authors.affiliation: University of Western Australia, Perth, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Moses
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: M
authors.initials: M
authors.lastname: Johnson
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: C
authors.initials: C
authors.lastname: East
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: T
authors.initials: T
authors.lastname: Dyer
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: L
authors.initials: L
authors.lastname: Roten
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: J
authors.initials: J
authors.lastname: Proffitt
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Fenstad
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Aalto-Viljakainen
authors.affiliation: Oulu University Hospital, Oulu, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Mäkikallio
authors.affiliation: Kuopio University Hospital, Kuopio, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Heinonen
authors.affiliation: National Institute for Health & Welfare, Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Kajantie
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Kere
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Laivuori
authors.affiliation: Norwegian University of Science & Technology, Trondheim, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Austgulen
authors.affiliation: Texas Biomedical Research Institute, San Antonio, United States.
authors.forename: J
authors.initials: J
authors.lastname: Blangero
authors.affiliation: University of Melbourne, Melbourne, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Brennecke