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Genetic analysis of >2000 cardiovascular candidate genes with pre-eclampsia in women of European, African-American and Hipanic Ancestry
Abstract Number: T-31
Abstract Type: Original Research
Introduction: Pre-eclampsia (PE), a common pregnancy disorder, can result in severe maternal and neonatal complications. It accounts for 10-15% of maternal deaths worldwide. PE also increases long-term maternal risk of cardiovascular diseases, including 4-fold increased risk of hypertension, and 2-fold increased risk of ischemic heart disease, stroke, and venous thromboembolism. The genetic basis of PE is unknown. Defining its causal genetic architecture should inform disease prediction, diagnosis, therapy and prevention of future cardiovascular risk.
Methods: To identify novel PE genes, we performed a multi-ethnic case-control study (n=640 cases/1,457 controls) using samples from 5 U.S academic medical centers. Genotypes were generated using a cardiovascular gene-centric SNP array comprising 2,000 genes selected based on prior genetic studies of cardiovascular diseases and on pathways expected to be important in cardiovascular disease. An additive genetic model with 10 principal components and clinical site of collection as covariates was used to test for genetic association in the European samples (516 cases/1,097 controls). For African-American (18 cases/67 controls) and Hispanic (106 cases/293 controls) samples, we assigned local ancestry at each genotyped position and employed a statistical framework combining SNP and admixture association, increasing power to detect genetic effects in these ethnic groups. Results across ethnicities were combined using a fixed-effects, inverse variance meta-analysis method. Pathway analysis was performed using a gene-set enrichment approach (MAGENTA).
Results: After quality control, 36,404 SNPs were available for association analysis in Europeans. No study-wide significant (P<2x10-6) associations were observed, but suggestive associations (P<10-5) were seen with SNPs in the genes Suppressor of Ty, domain containing 1 (S. cerevisiae) (SPTY2D1: OR (95%CI) 1.51 (1.27-1.80)) and pleckstrin homology domain containing, family G (with RhoGef domain) member 1 (PLEKHG1; 1.52 (1.26-1.82)). In multi-ethnic meta-analyses, the PLEKHG1 gene association retained strongest evidence of association, and additional suggestive signals at NRG3, PTGIS and GAB2 were observed. Pathway based analysis in Europeans highlighted ‘retinol dehydrogenase activity’ as the most significant gene ontology (GO term; p=3.0x10-4).
Conclusion: While replication studies are required to validate our findings, this study offers possible insights into the etiology of PE and demonstrates the added value of admixture analysis and multi-ethnic studies to the search for susceptibility genes for PE.