Association of VEGFR-1, 2, and 3 htSNPs with susceptibility to preeclampsia. S.M. Zeng¹, J. Yankowitz¹, J. Murray², D. Merrill³. 1) Dept OB/GYN, Univ Iowa Col Med, Iowa City, IA; 2) Dept Ped, Univ Iowa Col Med, Iowa City, IA; 3) Dept OB/GYN, Wake Forest College of Medicine, Winston-Salem, NC.
   Preeclampsia (PE) is a multiorgan, pregnancy-specific disorder, characterized by hypertension and proteinuria. PE is a major cause of maternal and neonatal mortality and morbidity worldwide. The etiology of PE remains unclear. Placental angiogenesis-related factors such as sFLT-1 (soluble fms-like tyrosine kinase 1), vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and their receptors including VEGFR-1 (FLT-1), VEGFR-2 (Flk or KDR) and VEGFR-3 (Flt-4) may be involved in PE pathogenesis. We previously performed a haplotype-based association study on VEGFR-1 and showed one SNP at intron 17 linked to PE risk. We hypothesize that some SNPs of VEGFR genes contribute to PE susceptibility.We investigated the association of VEGFR-1, -2 and -3 htSNPs with PE susceptibility. A haplotype-based association study was carried on in a Caucasian population including 564 patients with PE and 564 normal pregnant women. Diagnosis of PE was according to the standard criteria. The htSNPs were selected from HapMap (www.hapmap.org). We genotyped 3 htSNPs for upstream and 3 for downstream of VEGFR-1, 2 neighboring the htSNP previously linked to PE-risk, 6 htSNPs for VEGFR-2 and 4 htSNPs for VEGFR-3. Genotyping was performed using TaqMan-PCR assay. Over 400 patients and over 400 controls yielded clear genotype data for each htSNP.
   One htSNP upstream to VEGFR-1 and 1 in VEGFR-2 had a significant difference in genotype and allele frequencies between patients and controls. Both were in Hardy-Weinberg equilibrium (P0.05). The other 16 htSNPs had no significant difference in their allele and genotype frequencies between controls and patients (P0.05). The upstream htSNP is between VEGFR-1 and C13orf12, 27 kb upstream from VEGFR-1. The frequency of its minor allele C was significantly higher in the patients (472/890=0.530) than in the normal women (443/930=0.476) (P0.025). The VEGFR-2 htSNP is in intron 12. Its minor allele T had a significantly lower frequency in patients (270/826=0.327) than in controls (354/930=0.381) (P0.025).