A Possible Genetic Cause for Racial Disparities in Preeclampsia

It has been known for decades that African American women are at greater risk for preeclampsia and, startlingly, are three times more likely than European American women to die as a result. However, a unique genetic risk factor for preeclampsia in African Americans had never been identified.

New findings from a case-control study of nearly 700 pregnancies reveals that APOL1 gene variants are associated with increased risk for preeclampsia, a relatively common disorder that affects as many as 8% of pregnancies in the United States and can cause serious complications including fetal growth restriction, preterm birth, seizures and even death.

Leslie Bruggeman, PhD, a staff member in the Department of Inflammation and Immunity and lead author of the study, has spent many years investigating the APOL1 gene and its role in kidney disease, another condition that is more common among African Americans.

APOL1, like many genes, can be slightly different from person to person and these allelic variants are part of racial and ethnic differences in genetic studies. Two allelic variants for the APOL1 gene are associated with increased risk for chronic kidney disease and are only found in populations of African ancestry.

“These variants are a product of an evolutionary survival advantage,” said Dr. Bruggeman. “They are protective against parasitic infections common in Africa, like African sleeping sickness, but if someone inherits two allelic variants, with this parasitic protection comes increased risk for chronic kidney disease.”

The APOL1-preeclampsia association

Dr. Bruggeman’s latest findings, published in the journal BMC Medical Genetics, are a continuation of a serendipitous observation she and her colleagues, John O’Toole, MD, and John Sedor, MD, made during their studies related to kidney disease risk and APOL1 genotype.

Here, the group is the first to report a possible similar genetic connection to preeclampsia. Importantly, the study showed that the development of preeclampsia was determined by the APOL1 genotype of the infant, not the mother. “This means that the mother’s risk for preeclampsia depends on the APOL1 genotype that the child inherits from his or her father,” said Dr. Bruggeman.

The researchers examined biobank collected tissues (including placentas, umbilical cords and fetal membranes) and heath record information (including maternal medical history, demographics, previous pregnancy history, clinical data from the current pregnancy and more) for about 8,000 normal term and complicated pregnancies between 2005 and 2014. They compared APOL1 genotype and placental pathology between 282 normal and 395 preeclampsia pregnancies among self-identified African American women.

“This study was a true collaborative effort, leveraging the outstanding resources in maternal and fetal medicine research across the city, including Cleveland Clinic, Case Western Reserve University (CWRU), University Hospitals and MetroHealth Medical Center,” said Dr. Bruggeman.

She and her team at Cleveland Clinic, including Drs. O’Toole and Sedor, analyzed clinical data and tissue samples that were collected and tracked through a biobank established by University Hospitals pathologist, Raymond Redline, MD, an authority on placental pathology in preeclampsia and preterm birth. The biobank was funded as part of the March of Dimes Prematurity Research Center – Ohio Collaborative, a state-wide consortium of researchers at CWRU, Ohio State University and the University of Cincinnati. Collaborator Scott Williams, PhD, a population geneticist at CWRU with expertise in African population genetics, conducted the genetic analyses.

“Working together, we saw a significant association between preeclampsia and APOL1 genotype when the African ancestry alleles associated with kidney disease risk were present in the fetal DNA,” Dr. Bruggeman explained. “When considering all of the preeclampsia cases together, the risk for preeclampsia was most significant as a dominantly inherited trait, but when examining just the most severe preeclampsia cases that required a preterm delivery, the risk was inherited as a recessive or additive trait.”

More research is needed among larger cohorts to understand these findings, but the study shows that infants carrying copies of APOL1 risk variants may increase a mother’s chance for developing preeclampsia.

When considered with other studies reporting similar risk associations, Dr. Bruggeman says there is potential clinical utility in incorporating genetic screening tests for APOL1 among pregnant African American women to help clinicians predict at-risk pregnancies and determine for whom targeted therapies may be useful.

Support for the study was provided in part by the National Institutes of Health.