Genetics of Complex Diseases and Health Disparities

点击翻译按钮获取中文摘要

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. 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. Accomplishments: 1) Previously, we published the first report that APOL1 high-risk status of the fetus is associated with a two-fold higher risk of preeclampsia in the mother, accounting for approximately one eighth of pregnancies complicated by preeclampsia, a leading cause of fetal prematurity, low birth weight, and maternal and fetal morbidity and mortality. Preeclampsia is two-fold more common in Blacks compared to others. Under a life-course framework, given the strong link between preeclampsia and maternal 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. We have extended this finding and now have shown that fetal-maternal APOL1 allele mismatch is independently associated with increased preeclampsia risk in African Americans, but not Haitian blacks (Hong et al., AJKD, 2021). Interestingly, this suggests that carriage of variant APOL1 may come at a considerable reproductive fitness cost, in the form of increased fetal and maternal mortality and may provide a clue as to why these variants have only arisen to high frequency in West Africa, although they are highly protective against T.b.rhodesiense, the cause of acute HAT which is highly prevalent in East Africa. The lack of association by fetal genotype or allelic mismatch with preeclampsia in Haitian Blacks may be due to differences in structural racism, other environmental or physiological factors, or genetic background. This study 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. 2) The diagnosis of focal segmental glomerulosclerosis (FSGS) requires a renal biopsy which can be problematic in children and in some adults. 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 (submitted, 2021). 3)The prevalence the African-specific APOL1 risk alleles and their association with chronic kidney disease in Sub-Saharan African populations has not been well studied, and data is particularly lacking from rural areas and central Africa. In collaboration Drs. Jadoul and Masimango, whom I mentored, we assessed the prevalence of kidney disease in a rural setting of eastern Congo. CKD prevalence was higher in urban compared to rural settings and was primarily driven by the traditional risk factors (female sex, aging, HIV, hypertension, and diabetes) (KIReports, 2020 and BMC Nephrology, 2021). We found that APOL1 high-risk genotypes and sickle trait are independently associated with reduced kidney function (eGFR60 ml/min/176m2 and increased risk of renal injury (urine proteinuria). This study found that common, pathogenic-selected genetic factors contribute to CKD in the general population from central Africa. However, larger-scale genetic studies are needed to further expand our knowledge of distribution of APOL1 and SCT genetic variants and their association of renal outcomes among populations within Africa. This study will be submitted by the end of FY21. 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. 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). We investigated the genetic cause of hypouricemia from 7 unsolved cases from our previous whole exome study, where we found that about 90% of hypouricemia is explained by two SLC22A12 variants. The hypouricemia cases were from two independent cohorts: the Korean genome and epidemiology study (KoGES) and Korean Cancer Prevention Study (KCPS-II)). We identified a SLC2A9 (voltage sensitive uric acid transporter) compound heterozygote (p.Met155Val and p.Arg380Gly) in a case with hypouricemia. The novel nonsynonymous mutation specifies the codons p.Met155Val and p.Met126Val for the splice isoforms SLC2A9a and SLCA9b, respectively (submitted, under revision). Molecular dynamics showed that the missense variant p.Met155Val hinders uric acid transport through a defect of the outward open geometry. We also showed that this variant did *TRUNCATED*