Genetics of Complex Diseases and Health Disparities

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Coding variants in APOL1 protect against human African trypanosomiasis, but are responsible for major health disparities for kidney, preeclampsia and cardiovascular diseases that disproportionally affect people with African ancestry. We have developed an extensive network of intramural and extramural international collaborations to investigate the association of APOL1 renal risk variants with preeclampsia, a major cause of maternal and fetal death), cardiovascular disease, and chronic kidney disease. We are also collaborating with researchers at the NIDDK to understand the pathophysiology of APOL1 variant protein in preeclampsia and kidney disease. A major goal is to understand the environmental and genetic factors that affect penetrance of APOL1-only 20% of individuals carrying APOL1 high risk genotypes develop chronic kidney disease, likely because APOL1 requires a second hit for renal injury to manifest. However, we also find that APOL1 penetrance varies widely by genetic ancestry and across geographic regions. We are testing the hypothesis that genetic variants on European ancestry chromosomes exacerbate APOL1 penetrance, causing increased risk of renal and kidney disease in African x European admixed populations (ie. African Americans or black Latinos) while genetic factors on African ancestry chromosomes may attenuate APOL1 penetrance. Accomplishments: 1) The independent role of APOL1 risk variants as a risk factor for cardiovascular disease (CVD) is conflicted among studies. We contributed data generated by our laboratory in over 10,000 African Americans for a meta-analysis of APOL1 associations with incident CVD events, including coronary heart disease, myocardial infarction, stroke, and heart failure. Over 9 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have CVD at study enrollment. Individuals carrying two APOL1 risk variants had similar risk of CVD compared to individuals with zero or one variant. The risk of heart failure, myocardial infarction, coronary heart disease, stroke, and all-cause death considered individually was also similar by APOL1 genotype. This study, the largest conducted to date on the independent association of APOL1 kidney risk variants on CVD or death, suggests that APOL1 kidney risk variants are not associated with increased risk of CVD, independent of kidney disease (Grams et al, JASN, 2019). 3) Preeclampsia, disproportionately affecting Black women, is a leading cause of medically-indicated preterm delivery and risk for future hypertension and chronic kidney disease (CKD). Under a life-course framework, given the strong link between preeclampsia and CKD, we asked whether maternal and fetal APOL1 renal risk alleles can jointly influence preeclampsia risk. We further explored potential modifiers on APOL1- preeclampsia association in a longitudinal cohort study of 426 Black mother-infant pairs (213 with preeclampsia) from the Boston Birth Cohort with investigators at the Johns Hopkins University. When stratified by maternal country of origin, fetal APOL1 risk alleles were associated with an increased risk of preeclampsia among non-Haitian Blacks under recessive (OR=3.2, 95% CI=1.2-9.1, P=0.025) models, but not in Haitian Blacks. This study lends further support to the observation that fetal APOL1 renal risk alleles are associated with an increased risk of preeclampsia and underscores the need to better understand maternal-fetal interaction and their genetic and environmental factors as contributors to ethnic disparities in preeclampsia and subsequent CKD. 4) Elevated serum uric acid is a biomarker for cancer, progressive kidney disease, and all-cause mortality, while carriage of extremely low levels of serum uric acid is a risk factor for nephrolithiasis (kidney stones) and exercise-induced acute kidney injury. We used whole-exome sequencing (WES) to assess the feasibility for genetic diagnosis. We selected cases with extreme hypouricemia from a Korean urban cohort of 179,381 subjects without underlying conditions. WES were performed for the discovery of rare causal variants for hypouricemia. We identified two known recessive variants within SLC22A12 (p.Trp258*, pArg90His) in 24 out of 31 subjects (77.4%). In an independent cohort, we identified 50 individuals with hypouricemia and genotyped the p.Trp258* and p.Arg90His variants; 47 of the 50 (94%) hypouricemia cases were explained by only two mutations. This is the first study to show the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two ethnic-specific variants identified 87.7% (71/81) of Korean patients with monogenic hypouricemia (Cha et al. Sci Rep, 2019). Early genetic identification of constitutive hypouricemia may prevent acute kidney injury by avoidance of dehydration and excessive exercise. Increased serum uric acid levels cause gout and are associated with multiple diseases, including certain cancers. We performed a GWAS for serum uric acid levels in nearly 7000 Koreans and calculated polygenic risk scores. We validated the association of low-frequency variants and the polygenic risk score with SUA levels in 3,194 individuals thereby identifying two low-frequency and six common independent variants associated with SUA (Cho et al. Sci Rep, 2020). 6) APOL1 high-risk genotypes have also been shown to cause COVID-19-associated nephropathy, with similar histological features to HIVAN, a rapidly progressive form of focal segmental glomerulosclerosis identified nearly exclusively in individuals with untreated HIV of African ancestry-nearly 80% of individuals with HIVAN carry APOL1 high-risk genotypes. In a series of case studies, COVID-19-associated nephropathy has been identified in carriers of two APOL1 risk alleles. We are now initiating case-control studies to identify long-term renal outcomes in African Americans and Africans who experienced mild to severe COVID-19; our underlying hypothesis is that APOL1 high-risk genotypes will be associated with renal injury (proteinuria) and decline in kidney function. 7) The diagnosis of focal segmental glomerulosclerosis (FSGS) requires a renal biopsy which can be problematic in children and in some adults. Further, the mechanisms of FSGS and response to therapy are diverse. We used single cell RNA-sequencing (scRNA-seq) to explore the disease-related cellular signatures in the urine of FSGS subjects. Using single cell transcriptomic analysis of 23 urine samples from 12 FSGS subjects, we identified immune cells, predominantly monocytes, and renal epithelial cells, including podocytes. Further analysis revealed two subtypes consistent with M1 and M2 monocytes. We found similar transcriptional signatures of M1 and M2 monocytes in the single cell transcriptomic data of monocytes/macrophages from the previously published studies of melanoma, head and neck cancer and kidney allograft rejection. Urine podocytes showed high expression of marker genes for epithelial-to-mesenchymal transition (EMT). We selected the 17 most highly expressed genes from immune cells and 10 most highly expressed EMT genes from urine podocytes. Using transcriptomic data from kidney biopsies from the Nephrotic Syndrome Study Network (NEPTUNE), we found that these urine cell immune and EMT signature genes showed higher expression levels in FSGS biopsies compared to minimal change biopsies. The identification of monocyte subsets and podocyte expression signatures in FSGS subjects' urine samples suggests that urine cell profiling can serve as a diagnostic tool in the context of nephrotic syndrome. Further, this approach may aid in the development of novel biomarkers for FSGS and for identifying personalized therapies targeting particular molecular pathways in immune cells and podocytes.