C-allele of rs4769613 Near FLT1 Represents a High-Confidence Placental Risk Factor for Preeclampsia

Abstract

The variant rs4769613 T/C within the enhancer element near FLT1 , an acknowledged gene in preeclampsia, was previously identified as a risk factor for preeclampsia in the genome-wide association study (GWAS) targeting placental genotypes. We aimed to test the robustness of this association in 2 Estonian cohorts. Both placental sample sets HAPPY PREGNANCY (Development of novel non-invasive biomarkers for fertility and healthy pregnancy; preeclampsia, n=44 versus nonpreeclampsia, n=1724) and REPROMETA (REPROgrammed fetal and/or maternal METAbolism; 52/277) exhibited suggestive association between rs4769613[C] variant and preeclampsia (logistic regression adjusted for gestational age and fetal sex, nominal P <0.05). Meta-analysis across 2 samples (96/2001) replicated the genome-wide association study outcome (Bonferroni corrected P =4×10 -3 ; odds ratio, 1.75 [95% CI, 1.23–2.49]). No association was detected with gestational diabetes mellitus, preterm birth, and newborn parameters. Also, neither maternal nor paternal rs4769613 genotypes predisposed to preeclampsia. The exact role of placental rs4769613 genotype in the preeclampsia pathogenesis is to be clarified as no effect was detected on maternal baseline serum sFlt-1 (soluble fms-related receptor tyrosine kinase 1) levels. However, when placental FLT1 gene expression and maternal serum sFlt-1 measurements were stratified by placental rs4769613 genotypes, significantly higher transcript and biomarker levels were detected in preeclampsia versus nonpreeclampsia cases in the CC- and CT- (Student t test, P ≤0.02), but not in the TT-genotype subgroup. We suggest that rs4769613 represents a conditional expression Quantitative Trait Locus, whereby only the enhancer with the C-allele reacts to promote the FLT1 expression in unfavorable placental conditions. The study highlighted that the placental FLT1 rs4769613 C-allele is a preeclampsia-specific risk factor. It may contribute to early identification of high-risk women, for example, when genotyped in the cffDNA available in maternal blood plasma.

The humanFLT1regulatory element directs vascular expression and modulates angiogenesis pathwaysin vitroandin vivo

“…Indeed, the precise combination of transcriptional regulators that bind at the regulatory elements of the FLT1 locus are not well understood. However, a few studies have highlighted the importance of FLT1 cis -regulatory elements and suggested that disruptions in these non-coding regulators affect gene expression of FLT1 and its isoforms and can ultimately lead to disease (26,28,37,38).…”

“…Dysregulation of the FLT1 genes leads to vascular abnormalities and cardiovascular phenotypes in fish, mice and humans (23)(24)(25). Despite extensive study of FLT1 function, its regulatory network of enhancers has not been completely defined (26)(27)(28). How perturbations of these elements may alter the transcriptional regulation of FLT1 has yet to be determined.…”

A common 1.6 Mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans

“…The subgroup of ‘REPROMETA proven fathers’ (n=311) was recruited in 2006-2011 at the Women’s Clinic at Tartu University Hospital during the REPROMETA study (PI: M. Laan), originally designed to collect mother-father-placenta trios at delivery to investigate genetics of pregnancy complications ( 43, 44 ). In this study, the REPROMETA fathers represented reference men with proven fertility.…”

“…The reference sample of Estonian men (n=1,134) comprised healthy young men (n=499) and subjects with proven fatherhood (n=635) ( Table 1, Table S1). The cohort of 'Estonian young men' (n=499) was to collect mother-father-placenta trios at delivery to investigate genetics of pregnancy complications (43,44). In this study, the REPROMETA fathers represented reference men with proven fertility.…”

“…b Male partners of pregnant women (3); eight men had sperm counts < 39 x 10 6 ; for four men sperm analysis was not available. c Male cohort without fatherhood data (42); 47 men had sperm counts < 39 x 10 6 ; for nine men sperm analysis was not available d REPROMETA study recruited and sampled couples after delivery of their newborn; details in (43,44). n.d., not determined a Deletion subtype analysis was carried out for cases with available sufficient quantities of DNA.…”