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48: Allelic variations in angiogenic pathway genes are associated with preeclampsia

      Objective

      Alterations in the levels of angiogenic factors have been associated with the development of preeclampsia (PRE). Yet, there is a paucity of studies investigating allelic variants of genes controlling anti- and pro-angiogenic factors and PRE. This study investigates the association of allelic variations in genes in the angiogenic pathway and PRE.

      Study Design

      Cases with PRE and term controls were prospectively collected between 2005-2007. Maternal DNA was extracted from blood. Clinical data was obtained by chart abstraction. The Illumnina IBC array was used. 139 tagSNPs in 6 genes (VEGFA, VEGFB, VEGF C, FLT1, FLT4, ENG) were evaluated. SNPs deviating from HWE (p<0.001) in controls and those that were monomorphic in an ethnic group were not analyzed. MVLR was used to evaluate the association SNPs in angiogenic factor genes and PRE after controlling for maternal age. All models were evaluated in blacks and whites separately. Haplotype analyses were performed in genes with SNPs demonstrating a univariate association.

      Results

      We analyzed data from 606 women. 489 black women (305 cases) and 117 white women (32 cases) were evaluated. In black women, the FLT1 rs12584067 (1.55 [1.01-2.36], p=0.04) SNP and rs7335588 SNP (0.62 [0.41-0.94], p=0.02) were significantly associated with PRE A VEGFC gene haplotype was associated with a reduced odds of PRE (0.58 [0.41-0.81], p=0.002). Additionally, 1 ENG, 3 FLT1, and 1 VEGFA SNPs were nominally associated with PRE. In white women, FLT1 rs722503 2.12 [1.07-4.19], p=0.03), FLT4 rs307826 (3.06 [1.18-7.91], p=0.02) and VEGFC rs7664413 (0.49 [0.24-1.01], p=0.05) SNPs were significantly associated with PRE.

      Conclusion

      Allelic variations in select genes in the angiogenic pathway are associated with PRE. These genetic variations may alter protein levels and thus, explain the abnormal serum levels of sFlt, ENG and PlGF seen in some women with PRE. Further research is needed to understand the association among serum levels of angiogenic factors, genetic polymorphisms and etiology of PRE in order to best predict clinical disease.