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Bill and Melinda Gates Preeclampsia Project

APOL1: A newly identified risk factor for preeclampsia

Lead Investigators: Robert Davis MD, MPH and Claire L. Simpson, PhD

In two independent studies, we recently found that pregnant African-American (AA) women whose fetus has two high risk (HR) APOL1 variants have approximately twice the risk for preeclampsia compared to other pregnant AA women1. APOL1 encodes apolipoprotein L1 and provides innate immunity against most forms of African trypanosomes, but not the strains causing Human African trypanomiasis (HAT); two APOL1 coding variants extend this protection against trypansonomes causing HAT and are under balancing selection in West Africa. Up to 25% of individuals in West Africa and 13% of African Americans carry two HR variants (ie, are high risk). APOL1 HR status is also strongly associated with a diverse spectrum of kidney diseases among AA (with odds ratios ranging from 7 to 89), and accounts for much of the excess burden of kidney disease among AA compared to whites.

As our data suggest that a substantial fraction (approximately 1/8) of all preeclampsia in AA women may be associated with fetal APOL1 HR status, knowledge of APOL1status early in pregnancy may be useful for preeclampsia prediction and pregnancy risk stratification. In addition, due to the substantial clinical and public health impacts of APOL1 risk upon maternal and infant health, it is critical to better understand the epidemiology of the relationship between APOL1 risk alleles and preeclampsia, and to determine whether this association is modified by other factors such as malaria, HIV, and sickle cell (SC) trait or disease, all highly prevalent in West Africa. Of note, both HIV infection and SC trait interacts with, and substantially magnifies, the impact of APOL1 on kidney disease.

We will collaborate with investigators from Ghana (Ghana Health Services, Korle-Bu Teaching Hospital and H3Africa) and the Netherlands (UMC Utrecht) as part of their study, ‘Severe Pre-eclampsia adverse Outcome Triage (SPOT) score for women with pre-eclampsia remote from term: VALidation [of the miniPIERS/fullPIERS models] and development of a risk prediction model applicable in clinical practice] (SPOT-VAL study)’. This study (funded by the UMC Utrecht Global Health Scholarship) began recruitment December 2017 in Accra, Ghana. Ghana has one of the highest rates of preeclampsia in Africa and an APOL1 HR prevalence >20%. This study will enroll 800 women with preeclampsia at five referral hospitals in Accra over 12 months; we are now proposing to enroll these women along with 1600 controls in a study of APOL1 and preeclampsia.  

Our study’s overarching goal is to better quantify the relationship between fetal (and maternal) APOL1 status and preeclampsia, and ultimately to develop better low-cost methods to predict high risk pregnancies. In aim 1, we will attempt to replicate our original findings in this larger study, and further address whether fetal high-risk APOL1 status is associated with timing of preeclampsia onset, preeclampsia severity, preeclampsia-associated fetal growth restriction, and incident versus recurrent preeclampsia. In aim 2, we will assess whether HIV infection, malaria infection, and/or sickle cell trait or disease interacts with APOL1 to modify preeclampsia risk. We will also assess the impact of infant gender, BMI, and diabetes upon the APOL1-preeclampsia relationship. Finally, in aim 3, we will study fetal and maternal genetic modifiers of the relationship between APOL1 and preeclampsia using the recently developed pan-African Illumina chip array. As fetal genotype is not readily available for clinical risk prediction, we will evaluate low-cost methods to estimate fetal genotype so that these estimates can be used in SPOT-VAL prediction models.

May 26, 2022