The relationship between APOL1 risk variants and with preeclampsia and fetal outcomes

In people of African ancestry, carrying 2 Apolipoprotein L1 gene (APOL1) high-risk variants (G1/G1, G2/G2, or G1/G2) has been associated with increased risk of progressive chronic kidney disease, hypertension, HIV-associated nephropathy and focal segmental glomerulosclerosis. Recent studies suggest that the impact of APOL1 high-risk variants also affects pregnancy and fetal outcomes, including preeclampsia, low birth weight/prematurity, and small for gestational age status. Murine models report associations of APOL1 high-risk variants with structural placental pathologies and activation of various cellular pathways, although clinical studies to date do not identify a clear association between APOL1 high-risk variants and placental pathology, suggesting that a "second hit" may be required. Importantly, studies to date mostly find that fetal, but not maternal, APOL1 high-risk variants were associated with adverse outcomes. Important knowledge gaps include how APOL1 high-risk variants impact the placenta, the second hits relevant to APOL1 genotype and pregnancy outcomes, and appropriate evaluation protocols. In this review, we summarize the existing literature, knowledge gaps, and future research recommendations regarding APOL1 and preeclampsia and fetal outcomes.