(1067) Preeclampsia associated genetic variants near FLT1 are associated with elevated late pregnancy maternal serum sFLT1

It is hypothesized that increased placental release of soluble fms-like tyrosine kinase-1 (sFLT1) is causally related to the pathophysiology of preeclampsia (PE). Genome-wide association studies identified four PE-associated fetal variants near the FLT1 gene: rs4769612, rs4769613, rs7318880, and rs12050029, but previous studies have failed to show associations between these variants in the mother and sFLT1 levels in the first and second trimester of pregnancy. We sought to determine the association between maternal or fetal carriage of these variants and maternal circulating levels of sFLT1 across all three trimesters of pregnancy.

Study Design:

We analyzed data from the Pregnancy Outcome Prediction study, a prospective cohort of nulliparous women, where 3,968 mother-child pairs passed genotyping quality control. Maternal serum sFLT1 levels were measured at 12-, 20-, 28-, and 36 weeks of gestational age (wkGA) using a Roche Cobas e411 analyzer. In cross-sectional and longitudinal regression models, the dependent variable was the z-score of log-transformed sFLT1 at each wkGA or the change in z-score between 28- and 36wkGA, adjusted for fetal sex, age, BMI, maternal race/ethnicity, alcohol use, smoking, deprivation index, and the top 10 genetic principal components.

Results:

There was no association between the maternal variants and sFLT1 levels at any individual wkGA (P > 0.05). There was no association between fetal variants and sFLT1 levels at 12, 20 or 28wkGA (P > 0.05). However, all four fetal variants were positively associated with the sFLT1 z-score at 36wkGA (Figure 1). All maternal and fetal variants except rs12050029 were associated with increased change in the sFLT1 z-score from 28 to 36wkGA. Fetal associations with third trimester sFLT1 z-score change were consistently stronger than maternal associations (P < 1 × 10^-5).

Conclusion:

Fetal variants near FLT1 associated with an increased risk of PE are associated with higher maternal serum sFLT1 levels in the third trimester, supporting a causal role for placentally derived sFLT1 in the pathophysiology of PE.