Maternal APOL1 risk alleles show no independent association with preeclampsia risk in multi-ethnic study

BackgroundAPOL1 risk alleles are prevalent in individuals of West African ancestry and associated with increased risk of kidney disease. Although preeclampsia disproportionately affects women of Black ethnic backgrounds, evidence linking APOL1 alleles to preeclampsia remains conflicting. ObjectivesThe purpose of this study was to explore whether maternal APOL1 alleles contribute to preeclampsia risk and associated adverse pregnancy outcomes. Study designWe conducted a nested case-control study of 5210 pregnant women, including 745 preeclampsia cases and 949 controls of Black self-reported ethnicity, 1385 preeclampsia cases and 2131 controls of White self-reported ethnicity. APOL1 G1 and G2 risk alleles were directly genotyped on the Illumina Infinium(R) Global Screening Array. Associations with preeclampsia, early preeclampsia, recurrent preeclampsia, birthweight centiles and gestational age at delivery were examined using regression models assuming a recessive mode of inheritance with adjustment for established risk factors and stratification by self-reported ethnicity and genetically-determined ancestry. ResultsPresence of APOL1 risk alleles was almost exclusively observed in women of Black self-reported ethnicity. 168/949 controls (17.7%) and 133/745 cases (17.9%) carried two APOL1 risk alleles, and these women did not have a significantly increased risk of preeclampsia compared to those with zero or one APOL1 risk alleles in adjusted analyses (OR 1.00, 95% CI 0.76-1.29, p=0.972). When restricting analysis to women of Black self-reported ethnicity only, no association was observed between APOL1 genotype and preeclampsia risk (adjusted OR 0.94, 95% CI 0.61-1.25, p=0.673). When restricting analysis to women of pan-African genetically-determined ancestry only, also no association was observed between APOL1 genotype and preeclampsia risk (adjusted OR 1.00, 95% CI 0.76-1.32). No associations were found between number of APOL1 risk alleles and early preeclampsia, recurrent preeclampsia, birthweight centile or gestational age at delivery after adjustment for established risk factors and stratification by self-reported ethnicity or genetically-determined ancestry. ConclusionsMaternal APOL1 risk alleles do not independently influence preeclampsia risk or related adverse outcomes in a multi-ethnic pregnancy study. Future studies should examine whether fetal APOL1 genotypes, alone or in interaction with maternal genotypes, contribute to preeclampsia risk. At a GlanceA. Why was this study conducted?O_LIAPOL1 risk alleles are prevalent in West African ancestry populations and associated with kidney disease C_LIO_LIPreeclampsia disproportionately affects women of Black ethnicity C_LIO_LIPrevious studies showed conflicting evidence linking maternal APOL1 alleles to preeclampsia risk C_LI B. What are the key findings?O_LIIn 5,210 multi-ethnic women, maternal APOL1 risk alleles showed no independent association with preeclampsia or related adverse outcomes C_LIO_LIAssociations in unadjusted analyses reflected West African genetic ancestry rather than direct causation C_LI C. What does this study add to what is already known?O_LILargest genetic study of maternal APOL1 and preeclampsia in women of Black ethnicity (745 cases) C_LIO_LIDemonstrates APOL1 alleles serve as ancestry markers rather than causal variants C_LIO_LIHighlights need to examine fetal genotypes and gene-environment interactions C_LI