Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease
Johnson, MP and Brennecke, SP and East, CE and Dyer, TD and Roten, LT and Proffitt, JM and Melton, PE and Fenstad, MH and Aalto-Viljakainen, T and Makikallio, K and Heinonen, S and Kajantie, E and Kere, J and Laivuori, H and Austgulen, R and Blangero, J and Moses, EK and Pouta, A and Kivinen, K and Ekholm, E and Hietala, R and Sainio, S and Saisto, T and Uotila, J and Klemetti, M and Lokki, AI and Georgiadis, L, Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease, Molecular Human Reproduction, 19, (7) pp. 423-437. ISSN 1460-2407 (2013) [Refereed Article]
Copyright The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
Pre-eclampsia is an idiopathic pregnancy disorder promoting morbidity and mortality to both mother and child. Delivery of
the fetus is the only means to resolve severe symptoms. Women with pre-eclamptic pregnancies demonstrate increased risk for later life
cardiovascular disease (CVD) and good evidence suggests these two syndromes share several risk factors and pathophysiological mechanisms. To elucidate the genetic architecture of pre-eclampsia we have dissected our chromosome 2q22 susceptibility locus in an extended
Australian and New Zealand familial cohort. Positional candidate genes were prioritized for exon-centric sequencing using bioinformatics,
SNPing, transcriptional profiling and QTL-walking. In total, we interrogated 1598 variants from 52 genes. Four independent SNP associations
satisfied our gene-centric multiple testing correction criteria: a missense LCT SNP (rs2322659, P ¼ 0.0027), a synonymous LRP1B SNP
(rs35821928, P ¼ 0.0001), an UTR-3 RND3 SNP (rs115015150, P ¼ 0.0024) and a missense GCA SNP (rs17783344, P ¼ 0.0020). We replicated the LCT SNP association (P ¼ 0.02) and observed a borderline association for the GCA SNP (P ¼ 0.07) in an independent Australian
case –control population. The LRP1B and RND3 SNP associations were not replicated in this same Australian singleton cohort. Moreover,
these four SNP associations could not be replicated in two additional case –control populations from Norway and Finland. These four SNPs,
however, exhibit pleiotropic effects with several quantitative CVD-related traits. Our results underscore the genetic complexity of preeclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVDrelated risk factors.