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. 2018 Sep 6;103(3):367-376.
doi: 10.1016/j.ajhg.2018.08.002. Epub 2018 Aug 30.

Fetal-Not Maternal-APOL1 Genotype Associated with Risk for Preeclampsia in Those with African Ancestry

Kimberly J Reidy  1 , Rebecca C Hjorten  2 , Claire L Simpson  3 , Avi Z Rosenberg  4 , Stacy D Rosenblum  5 , Csaba P Kovesdy  6 , Frances A Tylavsky  7 , Joseph Myrie  1 , Bianca L Ruiz  1 , Soulin Haque  1 , Khyobeni Mozhui  8 , George W Nelson  9 , Victor A David  10 , Xiaoping Yang  4 , Masako Suzuki  11 , Jack Jacob  12 , Sandra E Reznik  13 , Frederick J Kaskel  1 , Jeffrey B Kopp  14 , Cheryl A Winkler  15 , Robert L Davis  16
Affiliations

Fetal-Not Maternal-APOL1 Genotype Associated with Risk for Preeclampsia in Those with African Ancestry

Kimberly J Reidy et al. Am J Hum Genet. .

Abstract

Black Americans are at increased risk for preeclampsia. Genetic variants in apolipoprotein L1 (APOL1) account for much of the increased risk for kidney disease in blacks. APOL1 is expressed in human placenta and transgenic mice expressing APOL1 develop preeclampsia. We evaluated the role of APOL1 variants in human preeclampsia. We determined maternal and fetal APOL1 genotypes in black women with preeclampsia in two populations. At Einstein Montefiore Center (EMC) Affiliated Hospitals, we studied 121 pregnancies in black women with preeclampsia. At University of Tennessee Health Science Center (UTHSC), we studied 93 pregnancies in black women with preeclampsia and 793 pregnancies without preeclampsia. We measured serum markers of preeclampsia soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). Fetal APOL1 high-risk (HR) genotype was associated with preeclampsia, with odds ratios at EMC and UTHSC of 1.84 (95% CI 1.11, 2.93) and 1.92 (95% CI 1.05, 3.49), respectively. Maternal APOL1 HR genotype was not associated with preeclampsia. Mothers with the fetal APOL1 HR genotype had more cerebral or visual disturbances (63% versus 37%, p = 0.04). In addition, fetal APOL1 HR genotype was associated with a higher sFLT-1/PlGF ratio at birth (p = 0.04). Fetal APOL1 high-risk genotype increases the risk for preeclampsia, likely by adversely affecting placental function. Further research is needed to assess whether APOL1 genetic testing can predict preeclampsia and improve pregnancy outcomes.

Keywords: APOL1; African American; fetal genotype; health disparity; preeclampsia; prematurity.

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Figures

Figure 1
Figure 1
APOL1 Genotype Association with Preeclampsia, by APOL1 Maternal and Fetal Genotype (A) Odds ratio and confidence intervals in the EMC, case-only population by fetal and maternal genotype. (B) Odds ratio and confidence intervals for the UTHMC, case-control population by fetal and maternal genotype. In both the EMC and UTHSC study populations, the presence of the fetal HR genotype resulted in a greater risk of developing preeclampsia. High-risk APOL1 genotypes are those with two risk alleles (G1/G1, G2/G2, and G1/G2). In the EMC cohort the crude odds ratio was calculated by median-unbiased estimation and exact confidence interval were calculated using the mid-p method. In the UTHSC cohort, odds ratios were performed using multivariate analyses and were adjusted for maternal age, household income, and child gender.
Figure 2
Figure 2
Soluble Serum Markers of Preeclampsia in Women with and without Preeclampsia in the UTHSC Case-Control Study, by Fetal APOL1 Genotype (A) At birth, mean sFlt-1 in women with preeclampsia and the fetal HR genotype was higher, the difference was not significant. (B) At birth, PlGF was markedly suppressed in women with preeclampsia and the fetal HR genotype (p value = 0.01). (C) At birth, the sFlt-1/PlGF ratio was significantly elevated in all women with preeclampsia, compared to all women without preeclampsia. However, the sFlt-1/PlGF ratio was significantly higher in preeclamptic mothers and the fetal APOL1 HR genotype when compared to preeclamptic mother’s with the fetal LR genotype at birth (p value 0.04). (E) There was an even more markedly elevated ratio of sFlt-1/PlGF at birth to the second trimester (or T1/T3) in these same mothers (p value 0.02). Scatterplot shows the mean and the standard deviation within each group. p values determined using a two-tailed, non-parametric Kruskal-Wallis test. ∗p value < 0.05.
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