Genome-Wide Association Scan Identifies a Risk Locus for Preeclampsia on 2q14, Near the Inhibin, Beta B Gene

Beta B Gene. PLoS ONE 7(3): e33666. doi:10.1371/journal.pone.0033666 Genome-Wide Association Scan Identifies a Risk Locus for Preeclampsia on 2q14, Near the Inhibin, Beta B Gene Matthew P. Johnson Shaun P. Brennecke Christine E. East Harald H. H. Go ring Jack W. Kent Jr. Thomas D. Dyer Joanne M. Said Linda T. Roten Ann-Charlotte Iversen Lawrence J. Abraham Seppo Heinonen Eero Kajantie Juha Kere Katja Kivinen Anneli Pouta Hannele Laivuori for the FINNPEC Study Group Rigmor Austgulen John Blangero Eric K. Moses Struan Frederick Airth Grant, The Children's Hospital of Philadelphia, United States of America Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, p = 3.5861027, OR = 1.57; rs12711941, p = 4.2661027, OR = 1.56) satisfied our genome-wide significance threshold (modified Bonferroni p,5.1161027). These SNPs reside in an intergenic region less than 15 kb downstream from the 39 terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r2 = 0.92), but not (r2,0.80) with any other genotyped SNP 6250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, p = 1.4861027, OR = 1.59) in strong LD with the two significant GWAS SNPs (r2.0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes 6500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ,250 kb centromeric to INHBB, and preeclampsia (p = 0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s). - Funding: National Institutes of Health grants supported the Australian GWAS (HD049847 to E.K.M., S.P.B. and J.B.) and MEDUSA, the super computer cluster at Texas Biomed (S10RR029392 to J.B.). The AT&T Genomics Computing Center at Texas Biomed is supported by the AT&T Foundation. Transcriptional profiling was supported by the Faye L. and William L. Cowden Charitable Foundation (to M.P.J.). The Norwegian cohort study was supported by the Functional Genomic Programme (FUGE) of the Norwegian Research Council (to R.A.). The FINNPEC study was supported by Jane and Aatos Erkko Foundation, Paivikki and Sakari Sohlberg Foundation, Academy of Finland, Research Funds of the University of Helsinki, Government Special Subsidiary for Health Sciences (EVO funding) at Helsinki and Uusimaa Hospital District. Novo Nordisk Foundation, Finnish Foundation for Pediatric Research, Emil Aaltonen Foundation, and Sigrid Juselius Foundation. M.P.J. is supported, in part, by an American Heart Association National Scientist Development grant (09SDG2350008). J.M.S. was supported by a Cornelius Regan Trust Award from the University of Melbourne. This investigation was conducted in facilities constructed with support from Research Facilities Improvement Program grant RR017515 from the National Center for Research Resources, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Preeclampsia is a common and serious complication of human pregnancy affecting 35% of all primigravid women [13]. Delivery of the fetus and placenta is the only intervention for adequate resolution of severe symptoms. It is a major cause of maternal mortality in developing countries, accounting for 50,000 maternal deaths yearly [4]. The maternal and fetal morbidity and mortality associated with preeclampsia and in particular with the adverse consequences of pre-term delivery are a major health burden in the developed world [57]. The pathophysiology of preeclampsia is thought to involve two main stages [8,9]. In stage one abnormal fetal-derived cytotrophoblast invasion in the uterine wall in early pregnancy is associated with failed remodeling of the maternal spiral arteries perfusing the placenta. This is thought to be a root cause. As a result of hypoxia and/or oxidative stress to the placenta there is release of syncytiotrophoblast-derived factors into the maternal circulation that give rise to the second stage of the maternal syndrome. The known placental factor of most relevance to this second stage is the soluble receptor for vascular endothelial growth factor, sVEGFR-1, also called sFlt-1. When present in excess, as in preeclampsia, sFlt-1 binds to, and activates, VEGF, a key survival factor for endothelium [10], and thereby induces systemic endothelial dysfunction. The principal diagnostic features of preeclampsia are new onset hypertension and proteinuria after 20 weeks gestation [11]. The hypertension is now recognized to be secondary to diffuse endothelial dysfunction [12], and the proteinuria is associated with glomerular endotheliosis [10,13]. Preeclampsia is therefore primarily characterized by endothelial dysfunction, which is also one of the principal pathogenic mechanisms in atherosclerotic vascular diseases such as coronary artery disease and stroke. Consistent with their shared pathogenesis, atherosclerosis and preeclampsia share many common risk factors including hypertension, obesity, insulin resistance, diabetes mellitus, metabolic syndrome, general inflammation, thrombophilia, and family history [14]. A history of preeclampsia increases the risk of future hypertension, ischemic heart disease, stroke and venous thromboembolism. This is true especially for women with a history of earlyonset preeclampsia (,34 weeks gestation) than those women who have preeclampsia at term [15]. A popular theory is that pregnancy provides a metabolic stress test to unmask underlying risk of cardiovascular disease [16]. These data have led several investigators to speculate [17,18] that the genetic risk factors for preeclampsia will also be relevant to cardiovascular disease, providing increased impetus and justification for their discovery [19,20]. By far the most effort to date has been focused on candidate genes, primarily those for which a plausible role in the known underlying pathophysio (...truncated)