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PubMed2024

Uncovering the health implications of abandoned mines through protein profiling of local residents.

Residents in areas with abandoned mines risk significant exposure to abundant heavy metals in the environment. However, current clinical indicators cannot fully reflect the health changes associated with abandoned mine exposure. The aim of this study was to identify biological changes in the residents of abandoned mine areas via proteomic analysis of their blood. Blood samples were collected from abandoned mine and control areas, and mass spectrometry was used for protein profiling. A total of 138 unique or common proteins that were differentially expressed in low-exposure abandoned mine area (LoAMA) or high-exposure abandoned mine area (HiAMA) compared to non-exposure control area (NEA) were analyzed, and identified 4 clusters based on functional similarity. Among the 10 proteins that showed specific change in LoAMA, 4 proteins(Apolipoprotein M, Apolipoprotein E, Apolipoprotein L1, and Cholesteryl ester transfer protein) were cluded in cluster 1(plasma lipoprotein remodeling), and linked to proteins that showed specific change in protein expression in HiAMA. Therefore, it is suggested that 4 proteins are changed at low exposure to an abandoned mine (or initial exposure), and then at high exposure, changes in various proteins involved in linked plasma lipoprotein remodeling are induced, which might triggered by the 4 proteins. Interestingly, in addition to plasma lipoprotein remodeling, proteins involved in other functional networks were changed in the high exposure group. These were all directly or indirectly linked to the 4 biomarkers(Apolipoprotein M, Apolipoprotein E, Apolipoprotein L1, and Cholesteryl ester transfer protein) that changed during low exposure. This suggests their potential utility in identifying areas impacted by abandoned mines. Especially, proteins involved in lipid metabolism and renal function-related diseases in individuals exposed to heavy metals in abandoned mine areas were correlated. Chronic kidney disease is predominantly instigated by cardiovascular disease and is commonly accompanied by dyslipidemia.

Humans↗
PubMed2026

Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant.

IMPORTANCE: The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual's M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored. OBJECTIVE: To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls. EXPOSURES: Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry. MAIN OUTCOME AND MEASURE: The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non-kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs). RESULTS: A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10-3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS. CONCLUSIONS AND RELEVANCE: In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.

Humans↗
PubMed2022

ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5 activation in a paradoxical biological circuit.

APOL1 risk variants are associated with increased risk of kidney disease in patients of African ancestry, but not all individuals with the APOL1 high-risk genotype develop kidney disease. As APOL1 gene expression correlates closely with the degree of kidney cell injury in both cell and animal models, the mechanisms regulating APOL1 expression may be critical determinants of risk allele penetrance. The APOL1 messenger RNA includes Alu elements at the 3' untranslated region that can form a double-stranded RNA structure (Alu-dsRNA) susceptible to posttranscriptional adenosine deaminase acting on RNA (ADAR)-mediated adenosine-to-inosine (A-to-I) editing, potentially impacting gene expression. We studied the effects of ADAR expression and A-to-I editing on APOL1 levels in podocytes, human kidney tissue, and a transgenic APOL1 mouse model. In interferon-γ (IFN-γ)-stimulated human podocytes, ADAR down-regulates APOL1 by preventing melanoma differentiation-associated protein 5 (MDA5) recognition of dsRNA and the subsequent type I interferon (IFN-I) response. Knockdown experiments showed that recognition of APOL1 messenger RNA itself is an important contributor to the MDA5-driven IFN-I response. Mathematical modeling suggests that the IFN-ADAR-APOL1 network functions as an incoherent feed-forward loop, a biological circuit capable of generating fast, transient responses to stimuli. Glomeruli from human kidney biopsies exhibited widespread editing of APOL1 Alu-dsRNA, while the transgenic mouse model closely replicated the edited sites in humans. APOL1 expression in mice was inversely correlated with Adar1 expression under IFN-γ stimuli, supporting the idea that ADAR regulates APOL1 levels in vivo. ADAR-mediated A-to-I editing is an important regulator of APOL1 expression that could impact both penetrance and severity of APOL1-associated kidney disease.

Humans↗
PubMed2026

DIA proteomics of FFPE renal biopsies reveals two molecular subtypes of lupus nephritis and identifies APOL1 as candidate biomarker for stratification.

INTRODUCTION: Lupus nephritis (LN) exhibits substantial clinical and pathological heterogeneity. We aimed to define proteomics-based molecular subtypes of LN and identify candidate biomarkers for subtype discrimination. METHODS: We analysed formalin-fixed paraffin-embedded (FFPE) renal biopsy specimens from 292 patients with biopsy-proven LN from four tertiary hospitals using data-independent acquisition (DIA)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics. Molecular subtypes were identified by non-negative matrix factorisation. Differential proteins, functional enrichment, immune pathway activity, protein-protein interaction networks and subtype-associated clinical/pathological features were evaluated. Extreme Gradient Boosting (XGBoost) with SHapley Additive exPlanations (SHAP) and Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression were used to identify key subtype-related features and derive a protein panel distinguishing proliferative (class III/IV) from membranous (class V) LN. RESULTS: Two stable molecular subtypes were identified, with 1002 differential proteins between them. Subtype_2 was enriched for interferon-related innate immunity, complement activation, phagocytosis-endocytosis-lysosome pathways and ribosome biogenesis/RNA metabolism, whereas Subtype_1 was characterised by keratinisation and epithelial structural remodelling. Subtype_2 was associated with higher serum creatinine, lower estimated glomerular filtration rate and higher chronicity index. APOL1 showed discriminatory value between subtypes, and serum ELISA demonstrated a consistent pattern with FFPE proteomic findings. A five-protein LASSO panel achieved an area under the curve of approximately 0.76 for distinguishing class III/IV from class V LN. CONCLUSION: DIA-based proteomic profiling of FFPE renal biopsies identifies biologically and clinically relevant LN molecular subtypes and may support tissue-informed classification and risk stratification.

Humans↗
PubMed2025

Clinical and Genetic Predictors of Sickle Cell Nephropathy: A Global Systematic Review.

Sickle cell disease (SCD) affects nearly 300,000 newborns annually worldwide, with 80% born in Africa. Sickle cell nephropathy (SCN) affects 5-18% of patients with SCD and contributes significantly to morbidity and mortality. Identifying SCN-associated factors would promote effective clinical management. We conducted a global systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (Prospective Register of Systematic Reviews, registration number: CRD42020185763) to explore clinical and genetic correlates of SCN. We sought after cohort, case-control, and cross-sectional studies published up to December 31, 2024 that reported on clinical and/or genetic predictors of SCN in different populations globally. A total of 70 hospital-based study articles were finally included, with a leading percentage (45.7%) of the included studies performed in the United States, whereas 24.3% were from Sub-Saharan Africa. Most had a cross-sectional design (68.6%) involving children and adults. Genetic studies (17/70) identified associations with α-thalassemia, APOL1, and HMOX1 genes. The only genome-wide association study identified six suggestive variants in CRYL1, VWF, ADAMTS7, LRP1B, linc02288, and FPGT-TNNI3K/TNNI3K among adult patients. In conclusion, this systematic review (1) unpacks and highlights the role of clinical, genetic, and biochemical factors in the pathogenesis and progression of SCN and (2) reveals the consistent association of SCN with the 3.7 Kb deletion in HBA and variants in APOL1 and HMOX1 genes. This systematic review underscores the paucity of data from Africa, emphasizing the need for large-scale prospective studies on African SCN cohorts. Our findings also provide a foundation for the early identification of individuals at risk for SCN and the avenues for clinical and public health management strategies. To the best of our knowledge, this is the first systematic review summarizing risk factors for kidney dysfunction in SCD populations worldwide, which includes, specifically, a meta-analysis for APOL1 association with albuminuria.

Humans↗
PubMed2025

Carrying APOL1 G1 allele is associated with cardiovascular complications during COVID-19 in an admixed population.

BACKGROUND: The APOL1 G1 and G2 alleles were selected in the Sub-Saharan African population by conferring resistance to trypanosome infection. However, these alleles are associated with kidney diseases, and their role in cardiovascular complications remains uncertain. A second hit mediated by an inflammatory state is necessary for APOL1-mediated phenotypes. Thus, this cross-sectional study investigates the association of APOL1 alleles with COVID-19 outcomes such as cardiovascular complications and kidney injury in an admixed population. Whole-genome sequencing was performed for 485 patients with different outcomes from a Biobank in Southern Brazil. RESULTS: COVID-19 individuals presented median age of 51 years, 281 were hospitalized, and 10.9% had CKD previous to the infection. Global ancestry inference revealed 12.8% of African ancestry. The G1 allele frequency was 2.7% and G2 allele was 1.2%. Local ancestry inference evidenced African ancestry in the locus of APOL1 alleles. The G1 allele frequency was higher among patients with severe outcomes. The presence of this allele was associated with kidney injury (OR = 2.78; 95% CI = 1.04-7.42; p = 0.041) using a minimally adjusted model and cardiovascular complications with a minimally (OR = 4.61; 95% CI = 1.61-13.19; p = 0.004) and fully adjusted model (OR = 4.59; 95% CI = 1.41-14.96; p = 0.011). Four individuals carried two alleles (three G1/G1 and one G1/G2) and three of them progressed to severe COVID-19 developing kidney injury. CONCLUSION: APOL1 risk alleles are present in the Brazilian population due to genetic admixture and the G1 allele was associated with COVID-19 outcomes.

Humans↗