APOL1 and Preeclampsia: Intriguing Links, Uncertain Causality, Troubling Implications

APOL1 and Preeclampsia: Intriguing Links, Uncertain Causality, Troubling Implications

Pre-eclampsia is associated with later kidney chronic disease and end-stage renal disease: Systematic review and meta-analysis of observational studies. Racial disparities in comorbidities, complications, and maternal and fetal outcomes in women with preeclampsia/eclampsia. Preeclampsia is a common, serious, multisystem disorder of pregnancy characterized by hypertension onset after 20 weeks of gestation (or worsening of hypertension in a patient with chronic hypertension) and onset or worsening of proteinuria. Data from the National Inpatient Sample showed approximately 177,000 of 3.8 million deliveries (4.7%) have a diagnosis of preeclampsia/eclampsia. This disorder is of interest to nephrologists, since women with chronic kidney disease (CKD) are at increased risk to develop preeclampsia and kidney physicians are often consulted to help manage their blood pressure and kidney manifestations. In addition, many but not all studies have suggested women with preeclampsia and normal kidney function have increased risk for later CKD and kidney failure, although absolute risk for kidney failure is under 1% within 20 years. Like CKD, preeclampsia is a health disparity. For Black women, the rate of preeclampsia is 60% higher than for White women, and the former have greater risk of maternal and fetal complications in the peripartum period.

Fetal – not maternal – APOL1 genotype associated with risk for preeclampsia in those with African ancestry. Maternal variants within the apolipoprotein L1 gene are associated with preeclampsia in a South African cohort of African ancestry. Association of preeclampsia with infant APOL1 genotype in African Americans. Joint associations of maternal-fetal APOL1 genotypes and maternal country of origin with preeclampsia risk. An investigation of APOL1 risk genotypes and preterm birth in African American population cohorts. Coding variants (called G1 and G2) in APOL1, the gene encoding apolipoprotein L1, associate with large effect sizes with a spectrum of nondiabetic kidney diseases in Black individuals. Several candidate gene association studies now have tested the hypothesis that the kidney risk variants (KRV) of APOL1 have pleiotropic effects and also contribute to the risk for preeclampsia (). Reidy and her colleagues first reported that fetal but not maternal APOL1 KRV associated with preeclampsia in Black women from 2 study locations. A subsequent study in South African women showed an association of the maternal G1 but not the G2 allele with early-onset, but not late-onset, preeclampsia. In Black women from a single center in Ohio, infant APOL1 genotype was significantly associated with preeclampsia. In this issue of AJKD, Hong et al have published the latest association study of APOL1 KRV in Black mother-infant pairs with and without preeclampsia. Using a nested case-control design and APOL1 alleles determined by direct genotyping, the study showed that neither infant nor maternal APOL1 KRV genotype associated with preeclampsia. When the cohort was stratified by maternal country of origin, fetal and maternal APOL1 KRV genotypes significantly associated with increased risk of preeclampsia in African American but not Haitian women. In addition, preeclampsia risk was higher with maternal-fetal APOL1 genotype discordance, an effect driven by the African American mother-infant pairs. An earlier analysis of publicly available data from this cohort had failed to associate maternal APOL1 KRV genotypes with preeclampsia risk, but this prior study had design limitations that Hong et al have addressed.

Preeclampsia risk is complex to dissect and is not only influenced by a mother’s demographic characteristics and comorbid conditions but also impacted by both the maternal and fetal genomes. In aggregate, these studies hint that both maternal and fetal APOL1 KRV may increase preeclampsia risk. However, beyond finding a significant odds ratio in at least 1 analysis in each study, the studies have significant inconsistencies in conclusions about the contribution of maternal APOL1 KRV alleles to preeclampsia risk and the genetic mode of inheritance for the APOL1 KRV association with preeclampsia risk. Sample sizes available to these investigative groups may have been limiting; the effect size of APOL1 KRV for preeclampsia risk appears to be similar to those described for other common traits rather than the large effect association of APOL1 KRV with kidney diseases. Given the potential clinical impact of a definitive association of APOL1 KRV with preeclampsia, investigators working in this area should consider collaboration for a meta-analysis. In addition, we know from empirical data that extended haplotypes appear to be important in mediating some APOL1 effects, and a more comprehensive analysis of APOL1 genetic variation and its association with preeclampsia risk could be informative.

Characterization of antibody specificities associated with preeclampsia. The significance of the placental genome and methylome in fetal and maternal health. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women. Hong et al have added several new twists to this evolving story. Their data suggest that the association of APOL1 KRV may be unique to African American Black individuals, at least when compared to risk in Haitians. Reasons for this discrepancy are not clear. Both Haitians and African Americans have predominantly West African ancestry and ancestry principal component analysis did not show significant differences in population structure by country of origin. Country of origin can be a surrogate for different cultural norms and traditions between groups, which presumably result in unique gene-environment interactions that increase preeclampsia risk only in African American women with APOL1 KRV. In another new finding, Hong et al have identified a discordance in maternal-fetal APOL1 genotypes associated with preeclampsia risk in African American but not Haitian women. Intriguingly, an agnostic screen using bacterial display peptides identified APOL1 autoantibodies that have been reported to associate with preeclampsia. Several studies have reported that other interactions between maternal and fetal genotypes increase preeclampsia risk. The variance in maternal contribution to preeclampsia risk between studies may reflect inadequate power to identify a modest effect size. In addition, mother and fetus share half their genomes, and variants associated with preeclampsia risk only in the fetal genome would have half the effect size in the mother and vice versa. None of the published studies assessed if the mother’s APOL1 genotype conferred preeclampsia risk independently of the fetal APOL1 genotype, although in African Americans both the maternal and fetal APOL1 KRV appear to increase risk if an APOL1 genotype discordance exists.

APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease. Fetal – not maternal – APOL1 genotype associated with risk for preeclampsia in those with African ancestry. APOL1-G0 or APOL1-G2 transgenic models develop preeclampsia but not kidney disease. Experimental data support the hypothesis that APOL1 KRV mediate preeclampsia. APOL1 levels, APOL1-derived peptides, and APOL1 autoantibodies have been linked to preeclampsia. Transgenic mice that expressed APOL1 using the nephrin (Nphs1) promoter developed a pregnancy-associated phenotype characterized by hypertension, proteinuria, and seizures, which was more severe in transgenic animals with an APOL1 KRV transgene compared to mice transgenic for reference APOL1. However this phenotype has not been described in other APOL1 transgenic mouse models driven by the endogenous promoter. Since nephrin is expressed in the placenta, the Nphs1:APOL1 mouse would recapitulate human placental APOL1 expression, which may have disrupted placentation from its cytotoxic effects. However, contrary to expectation, APOL1 KRV failed to associate with preeclamptic histopathologic placental phenotypes.

Perceived stress and self-rated health of Haitian and African Americans with and without Type 2 diabetes. The seen and the unseen: race and social inequities affecting kidney care. In closing, we would like to revisit the surprising discordance between African Americans and Haitians in APOL1 KRV association with preeclampsia risk. Known risk factors for preeclampsia were similar between groups, and a subset of participants in this study had comparable genetic ancestry. Society would label all these woman as Black, ostensibly eliminating race as a predictor of nongenetic factors regulating preeclampsia risk. However, one difference between these groups is the majority of Haitian woman studied by Hong et al have been in the United States less than 10 years, consonant with immigration patterns for all Haitians. Although Haitian Americans in 1 study have higher perceived stress than African Americans, these Haitian women have had a shorter exposure to the policies and social conditions, the structural racism, and the environmental contexts that through allostatic load and epigenetic pathways can manifest in biological responses and disease.

Preeclampsia is more prevalent in African Americans and their case fatality is 3 times higher than rates in White women. Genetics alone is unlikely to explain disparities in preeclampsia risk, but identification of genetic determinants has been hampered by the limited numbers of diverse patients in populations used for genome-wide association studies. To address this stark health inequality, we as a community, along with our Ob-Gyn colleagues, need to determine if APOL1 KRV unambiguously associates with preeclampsia risk in African American women and assess the clinical utility of this observation. Perhaps more importantly, we also need to advocate for strategies that address the unconscionable, root social factors responsible for biases in care of Black women.