APOL1 Genotype Research Articles

Associations between APOL1 Genotypes and Major Adverse Cardiovascular Events (MACE) in Proteinuric Glomerulopathies: A CureGN and NEPTUNE Study

Associations between APOL1 Genotypes and Major Adverse Cardiovascular Events (MACE) in Proteinuric Glomerulopathies: A CureGN and NEPTUNE Study

Potentiated JAK-STAT Signaling Differentiates Stem Cell-Derived Podocytes of Patients with APOL1-Associated FSGS from Those of Healthy Carriers with a High-Risk APOL1 Genotype

Potentiated JAK-STAT Signaling Differentiates Stem Cell-Derived Podocytes of Patients with APOL1-Associated FSGS from Those of Healthy Carriers with a High-Risk APOL1 Genotype

Increased risk of kidney failure in patients with genetic kidney disorders.

BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.

Prevalence of Mendelian Kidney Disease Among Patients With High-Risk APOL1 Genotypes Undergoing Commercial Genetic Testing in the United States

Among individuals with high-risk APOL1 genotypes, the lifetime risk of developing kidney failure is ∼15%, indicating that other genetic variants or nongenetic modifiers likely contribute substantially to an individual patient's risk of progressive kidney disease. Here, we estimate the prevalence and distribution of Mendelian kidney diseases among patients with high-risk APOL1 genotypes undergoing commercial genetic testing in the United States. We analyzed clinical exome sequencing data from 15,181 individuals undergoing commercial genetic testing for Mendelian kidney disease in the United States from 2020 to 2021. We identified patients with high-risk APOL1 genotypes by the presence of G1/G1, G1/G2, or G2/G2 alleles. Patients carrying single risk APOL1 alleles were identified as G1/G0, G2/G0; the remainder of patients were G0/G0. We estimated the prevalence and distribution of Mendelian kidney disease stratified by APOL1 genotype and genetically predicted ancestry. Of 15,181 patients, 3119 had genetic testing results consistent with a molecular diagnosis of Mendelian kidney disease (20.5%). Of 15,181 patients, 1035 (6.8%) had high-risk APOL1 genotypes. Among patients with recent genomic African ancestry, the prevalence of Mendelian kidney diseases was lower in those with high-risk APOL1 genotypes (9.6%; n= 91/944) compared with single risk APOL1 allele carriers (13.6%; n= 198/1453) and those with G0/G0 APOL1 genotypes (16.6%; n= 213/1281). Among patients with Mendelian kidney disease and recent genomic African ancestry, we observed differences in the prevalence of pathogenic/likely pathogenic variants in PKD1 (19.8% in high-risk vs. 30.2% in low-risk genotypes), and COL4A4 (24.2% in high-risk vs. 10.5% in low-risk genotypes). In this selected population of patients undergoing clinical genetic testing, we found evidence of Mendelian kidney disease in ∼10% patients with high-risk APOL1 genotypes.

#2213 APOL1 high-risk genotype in in a Dutch multi-ethnic population

Abstract Background and Aims The presence of 2 APOL1 high-risk alleles (high-risk APOL1 genotype) is associated with an increased risk of ESKD. In the USA, the prevalence of these high-risk alleles is high in people of West African descent and almost absent in patients from European descent. In Amsterdam, there is a significant number of people from Surinam, and (West-) Africa. A big group of Surinamese individuals have a West African heritage. The prevalence, however, of high-risk APOL1 genotype in the Netherlands and thereby the significance is unknown. The aim of this research was to investigate the prevalence of the APOL1 risk alleles in a multi-ethnic cohort of the Amsterdam general population consisting of individuals of African Surinamese, Ghanaian, Moroccan and Dutch origin. Second we correlate the presence of these risk alleles to blood pressure, kidney function and proteinuria. Method HELIUS is a multi-ethnic prospective cohort study including people aged 18-70 who were randomly selected, stratified by ethnic origin, from the Amsterdam general population. Baseline examination took place tween 2011 and 2015. We analysed a population of 5971 individuals with available genotype data, of whom 1287 were of Dutch, 3048 of Moroccan, 1156 of African Suriname and 480 of Ghanaian descent. APOL1 risk was determined by genotyping two APOL1 missense variants, rs73885319A>G, S342G; rs60910145T>G, I384M, together constitute the G1 high-risk allele and the 6-base pair deletion allele, rs71785313 RRRATAA/−, N388Y399/−−, is the G2 high risk allele. Logistic regression analyses were performed to determine correlation between creatinine, eGFR, and systolic blood pressure and apol1 high risk genotype, with additional adjustments for age, sex, and BMI. Results The prevalence of high-risk APOL1 genotype was 4.17% in the total sample, in African Surinamese 9.5%, and in the Ghanaian 29.0%. There were no individuals with high risk genotype in the Moroccan or Dutch descent population. The presence of high risk APOL1 genotype was associated with an elevated creatinine level of 10.68 µmol/L (SD 0.91) in the whole cohort. Also, in the Surinamese and Ghanaian populations population the presence of the high-risk APOL1 genotype was associated with an increased creatinine of 2.6 µmol/L (SD 1.00) as compared to the black population with low-risk APOL1 genotype. People with high-risk APOL1 genotype had significantly higher systolic blood pressure 10.69 mmHg (SD 0.091) than those without. Nevertheless, there was no significant difference in systolic blood pressure in the black population with high-risk APOL1 genotype in comparison with the black population with low-risk APOL1 genotype 1.38 mmHg (SD 1.17). Also, there was no significant difference in eGFR (CKD CKD-EPI 2009) in any analysis and no differences in proteinuria was seen, between those with and without the high-risk APOL1 genotype. Conclusion In this population, the overall prevalence of the APOL1 risk alleles seems to conform to the African American population in the USA. There is however a much higher prevalence of high-risk APOL1 genotype in the Ghanaian in comparison to the African Surinamese. The group with high-risk APOL1 genotype had significantly higher creatinine levels and higher systolic blood pressure. However there was no significant difference in blood pressure within the black population between APOL1 high-risk genotype and low-risk genotype. There was no significant difference in eGFR, possibly because the CKD-EPI 2009 formula was used which overestimates the eGFR in the black population. Better calculation with cysteine C possibly gives different outcomes. In conclusion, this is the first study in Europe investigating the prevalence of APOL1 high-risk genotype in a large population-based cohort. APOL1 risk alleles, and high-risk genotype, are prevalent in our population of African descent. More analysis in this cohort are pending and also longitudinal data will follow.

#1003 Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of AZD2373, an antisense oligonucleotide targeting APOL1

Abstract Background and Aims APOL1 mediated kidney disease (AMKD) is associated with toxic gain of function variants in people of African ancestry carrying the high-risk APOL1 genotypes (G1 and G2). APOL1 protein is part of the innate immune system but not considered essential. AZD2373, an antisense oligonucleotide that targets APOL1 mRNA to reduce its protein synthesis, is in development for AMKD. In genomic APOL1-transgenic mice, AZD2373 reduced APOL1 expression in kidney and liver, reduced plasma APOL1 protein concentration, and prevented development of IFN-γ induced proteinuria in high-risk genotype mice. In a single ascending dose study (NCT04269031), AZD2373 was well tolerated. We assessed the safety and tolerability of AZD2373 in a multiple ascending dose study including pharmacokinetics, and pharmacodynamic effect on APOL1 plasma protein levels. Method In this phase 1, randomized, single-blind, placebo-controlled study (NCT05351047) in healthy male volunteers of West African ancestry, participants were enrolled after a pre-screening study where they were genotyped for APOL1 prospectively; 18 participants had either 1 copy or 2 copies of the G1/G2 APOL1 high-risk allele. Low, medium and high dose cohorts each with 8 participants each receiving six weekly subcutaneous injections of either AZD2373 (n = 6) or placebo (n = 2) and were subsequently followed up for 9-weeks post-last dose. The primary objective was safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD2373. Results In total, 24 participants were randomized and completed the study. No major safety and tolerability concerns were reported up to the highest dose of AZD2373 administered. The most common adverse event was injection site reactions which were dose-dependent, mild to moderate in severity and did not lead to treatment discontinuation. After dosing, AZD2373 had a rapid distribution phase (hours) and prolonged elimination phase (days to weeks). Clearance was similar across dose levels after single and repeated dosing, and the renal contribution to overall clearance was minimal. Exposure generally increased in a dose proportional manner. Plasma APOL1 was knocked down in a dose dependent manner (Figure). Conclusion Repeated doses of AZD2373 were safe and well tolerated, reducing plasma APOL1 concentrations in a dose- and time-dependent manner in healthy males of West African ancestry.

#832 Sickle cell trait and APOL1 high risk genotype increase the risk of ESKD similar to diabetes in British Africans

Abstract Background and Aims Little is known of the risk of end-stage kidney disease (ESKD) in British Africans with Sickle Cell Trait or APOL1 High-risk genotypes. We aim to determine the prevalence of the APOL1 high-risk genotype and genetically defined Sickle Cell Trait in British Africans and their association with ESKD. Method We analysed 7380 British Africans from a UK population cohort, UK Biobank. It contains deep phenotypes, biomarkers, and DNA sequence data. We used whole exome sequencing data to identify carriers of known APOL1 high risk genotypes (G1G1, G1G2, G2G2) and SCT (heterozygous carriers of p.Glu7Lys in HBB). We identified individuals with ESKD (in receipt of renal replacement therapy including kidney transplant) using self-report, hospital admissions records, and general practice records. We used a cox proportional hazard model to determine the risk of ESKD with these genotypes adjusted for age, sex, hypertension, smoking and diabetes. Results 1131/7380 (17.9%) British Africans carry the APOL1 High risk genotype whereas 860/7380 (14.3%) had genetically defined SCT. Both risk states were found in 216/7380 individuals. Together, 32.2% carry one or both of these variants and 36/2207 (1.6%) developed ESKD. Of those with neither SCT nor APOL1 HR genotype 32/5173 (0.67%) developed ESKD. The multivariable cox-proportional hazard model showed that APOL1 high risk genotype increased the risk of ESKD by two-fold (HR 2.12-95% CI 1.19-3.79), p = 0.011. Surprisingly, the risk of ESKD was also two-fold higher in SCT carriers (HR 2.59 95% CI 1.44-4.68), p = 0.002 independent of APOL1 genotype. This risk was of ESKD for people with either SCT or the APOL1 high risk genotype was similar to that associated with diabetes (HR 2.75 95% 1.58-4.80), p < 0.001. The polygenic score for eGFR did not change the risk of ESKD in these carriers. Conclusion We show for the first time that 1 in 3 British Africans carry either two APOL1 high-risk variants or sickle cell trait, both of which double the risk of ESKD. These genetic risk factors increase the risk of developing ESKD to a level similar to that resulting from diabetes. A sensible starting point would be a trial of screening and aggressive management of conventional risk factors for ESKD.

373 Renal transplant failure secondary to COVID-19 associated collapsing glomerulopathy and presence of APOL-1 genotype

373 Renal transplant failure secondary to COVID-19 associated collapsing glomerulopathy and presence of APOL-1 genotype

Variant focal segmental collapsing glomerulosclerosis associated with COVID-19 vaccine and highrisk APOL1 genotype clinical case report and bibliographic review

Introduction: The COVID-19 pandemic, produced by a mutant strain of coronavirus SARS-CoV-2, which caused worldwide chaos never seen before, started in China in December 2019. In Brazil the first case was confirmed on February 26, 2020 with a 61-year -old patient and the World Health Organization declared a pandemic on March 11, 2020; the aggressiveness of the disease led to an accelerated search for treatments and vaccines, just in July 2021, there were 184 vaccine candidates against COVID-19; Along with immunization, several adverse effects generated by the various vaccines have been reported, ranging from mild to severe, from minor pain at the puncture site to headache, fever, arthralgias, etc. Severe cases have also been reported, such as anaphylaxis, heart disease, renal alterations, etc. which to date are not fully determined. Clinical case: It is related to a clinical case report in Brazil of a 16-year-old female patient, with no significant personal history, who received the first dose of the vaccine for COVID-19 (Pfizer-BioNtech) and 3 days later presented with headache, abdominal pain and arterial hypertension; when assessed and with complementary examinations was determined a rapidly progressive glomerulonephritis, she received treatment with corticosteroids for 3 days; with the biopsy resulted in focal and segmental collapsing glomerulosclerosis with moderate tubulointerstitial repercussion (30-40%). Evolution: The patient developed renal failure and nephritic/nephrotic syndrome. Conclusion: It is not determined with certainty, but there is the possibility of association of glomerular disease with vaccination for COVID-19, it is necessary to continue with the vaccination campaigns and to reduce the aggressiveness of this disease.

Phenome-wide analysis reveals epistatic associations between APOL1 variants and chronic kidney disease and multiple other disorders

APOL1 variants G1 and G2 are common in populations with recent African ancestry. They are associated with protection from African sleeping sickness, however homozygosity or compound heterozygosity for these variants is associated with chronic kidney disease (CKD) and related conditions. What is not clear is the extent of associations with non-kidney-related disorders, and whether there are clusters of diseases associated with individual APOL1 genotypes. Using a cohort of 7462 UK Biobank participants with recent African ancestry, we conducted a phenome-wide association study investigating associations between individual APOL1 genotypes and conditions identified by the International Classification of Disease phenotypes. We identified 27 potential associations between individual APOL1 genotypes and a diverse range of conditions. G1/G2 compound heterozygotes were specifically associated with 26 of these conditions (all deleteriously), with an over-representation of infectious diseases (including hospitalisation and death resulting from COVID-19). The analysis also exposed complexities in the relationship between APOL1 and CKD that are not evident when risk variants are grouped together: G1 homozygosity, G2 homozygosity, and G1/G2 compound heterozygosity were each shown to be associated with distinct CKD phenotypes. The multi-locus nature of the G1/G2 genotype means that its associations would go undetected in a standard genome-wide association study. Our findings have implications for understanding health risks and better-targeted detection, intervention, and therapeutic strategies, particularly in populations where APOL1 G1 and G2 are common such as in sub-Saharan Africa and its diaspora. This study was funded by the Wellcome Trust (209511/Z/17/Z) and H3Africa (H3A/18/004).

APOL1 Risk Variants Associate With the Prevalence of Stroke in African American Current and Past Smokers.

African American smokers have 2.5 times higher risk for stroke compared with nonsmokers (higher than other races). About 50% of the African American population carry 1 or 2 genetic variants (G1 and G2; rare in other races) of the apolipoprotein L1 gene (APOL1). Studies showed these variants may be associated with stroke. However, the role of the APOL1 risk variants in tobacco-related stroke is unknown. In a cross-sectional study, we examined whether APOL1 risk variants modified the relationship between tobacco smoking and stroke prevalence in 513 African American adults recruited at University of California, San Francisco. Using DNA, plasma, and questionnaires we determined APOL1 variants, smoking status, and stroke prevalence. Using logistic regression models, we examined the association between smoking (ever versus never smokers) and stroke overall, and among carriers of APOL1 risk variants (1 or 2 risk alleles), and noncarriers, separately. Among participants, 41% were ever (current and past) smokers, 54% were carriers of the APOL1 risk variants, and 41 had a history of stroke. The association between smoking and stroke differed by APOL1 genotype (Pinteraction term=0.014). Among carriers, ever versus never smokers had odds ratio (OR) 2.46 (95% CI, 1.08-5.59) for stroke (P=0.034); OR 2.00 (95% CI, 0.81-4.96) among carriers of 1 risk allele, and OR 4.72 (95% CI, 0.62-36.02) for 2 risk alleles. Among noncarriers, smoking was not associated with a stroke. Current and past smokers who carry APOL1 G1 and/or G2 risk variants may be more susceptible to stroke among the African American population.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study.

Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis. Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70-1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21-2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74-1.81; p=0.52]). APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study

Background:Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease.Methods:A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis.Results:Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00–1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88–1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70–1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21–2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00–1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74–1.81; p=0.52]).Conclusions:APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease.Funding:This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

#3155 APOL1 GENOTYPE IS A MAJOR DETERMINANT OF LUPUS NEPHRITIS SEVERITY IN PATIENTS OF AFRICAN ANCESTRY

Abstract Background and Aims Two polymorphisms of APOL1 gene, G1 and G2, exclusively found among patients of African ancestry, have been associated with chronic kidney disease (CKD) and end-stage kidney disease (ESKD)1. These high-risk polymorphisms have also been associated with collapsing glomerulopathy in various diseases. We aimed to evaluate the impact of APOL1 G1 and G2 polymorphisms on the clinical and pathological course LN which is already known to be more severe among patients of African ancestry2. Method We included patients from 6 hospitals in Paris and Marseille in France, between January 2017 and March 2020, with biopsy-proven LN, African ancestry and age >18 years at the time of inclusion. We excluded those with HIV infection. The data were retrospectively collected at LN diagnosis, 1 year after diagnosis and at last follow-up. APOL1 genotyping was performed and we divided patients in 2 groups: the high-risk genotype (HRG) group with 2 risk alleles and the low risk genotype (LRG) group with 1 or 0 risk allele. All patients signed a consent form for the genetic analysis and protocol approval was obtained from the ethic committee CERAPHP (Comité d'Ethique de la Recherche AP-HP Centre), registration number 00011928. Results Ninety-nine patients were included in the study, 13 in the HRG group and 86 in the LRG group. The median duration between LN diagnosis and inclusion in the study was 9.6 years [4.9-16.9]. At LN diagnosis, clinical and biological characteristics were similar except for kidney function that was lower in the HRG group compared to the LRG group with a median serum creatinine of 131μmol/L [69-687] versus 66μmol/L [52-133] (p = 0.0085). Patients in the HRG group were more likely to have a serum creatinine above 200 μmol/L compared to the LRG group (45.5% versus 10.5%, p = 0.0096, OR 7.1[1.8-28.6]), and required acute haemodialysis more frequently (30.8% versus 1.3% respectively, p = 0.0012, OR 34.7[3.5-345.1]). Collapsing glomerulopathy was more frequent in the HRG group (45.5% of patients, versus 4.5%, OR 17.5[3.3-91.9], p = 0.001). No significant difference was observed in the proportion of kidney response at 12 months, however, patients in the HRG group were more likely to develop CKD (33.3% versus 4.9%, OR 9.6[2.0-46.1]). Median follow-up from LN diagnosis to the end of study, ESKD or last follow-up was 7.9 years [3.4-13.3] and was similar between the 2 groups. At last follow-up, median eGFR was 22mL/min/1.73m2 [10-98] vs 99mL/min/1.73m2 [55-118] respectively, p = 0.0189. Survival without ESKD was poorer in the HRG group than in the LRG group with a hazard ratio (HR) of 5.0[1.6-15.8], p = 0.006, even after adjusting with the kidney response at 12 months (adjusted HR 6.24[1.8-21.6], p = 0.004) (Figure 1). Conclusion APOL1 genotype affects LN prognosis, resulting in a worse kidney function at diagnosis, development of collapsing glomerulopathy and higher risk of subsequent ESKD. Kidney survival remained significantly lower in the HRG group, after adjustment for kidney response at 12 months, suggesting that the prognosis of LN is heavily driven by APOL1 genotype regardless of the kidney response. APOL1 inhibitors are currently being developed, and could be used in the next future, for HRG patients with primary or secondary forms of collapsing glomerulopathy.

Clinical and Genetic Characteristics of CKD Patients with High-Risk APOL1 Genotypes.

APOL1 high-risk genotypes confer a significant risk of kidney disease, but variability in patient outcomes suggests the presence of modifiers of the APOL1 effect. We show that a diverse population of CKD patients with high-risk APOL1 genotypes have an increased lifetime risk of kidney failure and higher eGFR decline rates, with a graded risk among specific high-risk genotypes. CKD patients with high-risk APOL1 genotypes have a lower diagnostic yield for monogenic kidney disease. Exome sequencing revealed enrichment of rare missense variants within the inflammasome pathway modifying the effect of APOL1 risk genotypes, which may explain some clinical heterogeneity. APOL1 genotype has significant effects on kidney disease development and progression that vary among specific causes of kidney disease, suggesting the presence of effect modifiers. We assessed the risk of kidney failure and the eGFR decline rate in patients with CKD carrying high-risk ( N =239) and genetically matched low-risk ( N =1187) APOL1 genotypes. Exome sequencing revealed monogenic kidney diseases. Exome-wide association studies and gene-based and gene set-based collapsing analyses evaluated genetic modifiers of the effect of APOL1 genotype on CKD. Compared with genetic ancestry-matched patients with CKD with low-risk APOL1 genotypes, those with high-risk APOL1 genotypes had a higher risk of kidney failure (Hazard Ratio [HR]=1.58), a higher decline in eGFR (6.55 versus 3.63 ml/min/1.73 m 2 /yr), and were younger at time of kidney failure (45.1 versus 53.6 years), with the G1/G1 genotype demonstrating the highest risk. The rate for monogenic kidney disorders was lower among patients with CKD with high-risk APOL1 genotypes (2.5%) compared with those with low-risk genotypes (6.7%). Gene set analysis identified an enrichment of rare missense variants in the inflammasome pathway in individuals with high-risk APOL1 genotypes and CKD (odds ratio=1.90). In this genetically matched cohort, high-risk APOL1 genotypes were associated with an increased risk of kidney failure and eGFR decline rate, with a graded risk between specific high-risk genotypes and a lower rate of monogenic kidney disease. Rare missense variants in the inflammasome pathway may act as genetic modifiers of APOL1 effect on kidney disease.

APOL1 Gene Variants and Risk for Cardiovascular Disease

Introduction: The association of APOL1 risk variants with cardiovascular risk and cardiovascular disease (CVD) in observational and clinical trials has had inconsistent results. We aim to assess the relationship between the presence of APOL1 risk variants and the CVD risk in Afro-descendant patients with end-stage renal disease (ESRD). Methods: We performed an observational, cross-sectional study of Afro-descendant adult patients with ESRD who were on the waitlist for a kidney transplant. Associations of APOL1 genotypes (high-risk [HR] = 2 alleles; low-risk [LR] = 0 or 1 allele) with cardiovascular risk were the primary clinical endpoint. The relation was evaluated using univariate and multivariate analysis. Results: We enrolled a total of 102 patients with ESRD; 37% (38 patients) had APOL1 HR status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form and 63% (64 patients) had APOL1 LR status. No significant association was found between HR APOL1 genotypes and high cardiovascular risk (in adjusted Colombia Framingham Risk Score). APOL1 HR versus LR variants were not independently associated with left ventricular hypertrophy or systolic dysfunction. No cardiovascular deaths occurred during the follow-up. Conclusion: In Afro-descendent patients with ESRD, APOL1 HR status is not associated with the increase in cardiovascular risk profile and metabolic disturbances.

APOL1 genotype associated risk for preeclampsia in African populations: Rationale and protocol design for studies in women of African ancestry in resource limited settings.

Women of African ancestry are highly predisposed to preeclampsia which continues to be a major cause of maternal death in Africa. Common variants in the APOL1 gene are potent risk factor for a spectrum of kidney disease. Recent studies have shown that APOL1 risk variants contribute to the risk of preeclampsia. The aim of the study is to understand the contribution of APOL1 risk variants to the development of preeclampsia in pregnant women in Ghana. The study is a case-control design which started recruitment in 2019 at the Korle Bu Teaching Hospital in Ghana. The study will recruit pregnant women with a target recruitment of 700 cases of preeclampsia and 700 normotensives. Clinical and demographic data of mother- baby dyad, with biospecimens including cord blood and placenta will be collected to assess clinical, biochemical and genetic markers of preeclampsia. The study protocol was approved by Korle Bu Teaching Hospital Institutional Review Board (Reference number: KBTH-IRB/000108/2018) on October 11, 2018. As of December 2021, a total of 773 mother-baby pairs had been recruited and majority of them had complete entry of data for analysis. The participants are made up of 384 preeclampsia cases and 389 normotensive mother-baby dyad. The mean age of participants is 30.69 ± 0.32 years for cases and 29.95 ± 0.32 for controls. Majority (85%) of the participants are between 20-30years. At booking, majority of cases had normal blood pressure compared to the time of diagnosis where 85% had a systolic BP greater than 140mmHg and a corresponding 82% had diastolic pressure greater than 90mmHg. Our study will ultimately provide clinical, biochemical and genotypic data for risk stratification of preeclampsia and careful monitoring during pregnancy to improve clinical management and outcomes.

Apolipoprotein L1 gene variants and kidney disease in patients with HIV: a systematic review and meta-analysis.

The risk of various types of kidney disease is significantly increased in the presence of APOL1 high-risk genotype (carriage of two risk alleles), particularly HIV-associated nephropathy (HIVAN). However, there are discrepancies in the existing evidence about the level of association between APOL1 high-risk genotype and the risk of kidney diseases in people living with HIV (PLWHIV). This systematic review and meta-analysis was conducted to assess the relationship between the APOL1 genotypes and kidney disease in the HIV population. An a priori protocol registered on PROSPERO (ID: CRD42021253877), was followed by a systematic search of five electronic databases. Database-specific search terms were used to identify observational studies that evaluated the outcomes chosen inthe review, based on a set of prespecified eligibility criteria. Using a random effect model, the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were pooled for the meta-analysis. After screening 4418 citations, 14 articles comprising 11,069 participants were included in this review. The risk of chronic kidney disease (CKD) in the HIV positive population was significantly increased in the presence of two APOL1 risk alleles (OR 4.65 [95% CI 3.51-6.15]). Also, a significant association was observedbetween the carriage of two risk APOL1 variants and proteinuria (OR 2.58 [95% CI 2.05-3.25]), HIVAN (OR 16.67 [95% CI 10.22-27.19]), and progression to end-stage kidney disease (ESKD) hazard ratio: 1.79 (95% CI 1.20-2.66). This review highlights a strong association between the presence of two risk APOL1 variants and an increased risk of kidney disease in PLWHIV, and provides a more precise estimate of the effect size, with smaller 95% CIs for CKD, HIVAN, and progression to ESKD.

Transcriptomic Analysis of Human Podocytes In Vitro: Effects of Differentiation and APOL1 Genotype

The mechanisms in podocytes that mediate the pathologic effects of the APOL1 high-risk (HR) variants remain incompletely understood, although various molecular and cellular mechanisms have been proposed. We previously established conditionally immortalized human urine-derived podocyte-like epithelial cell (HUPEC) lines to investigate APOL1 HR variant-induced podocytopathy. We conducted comprehensive transcriptomic analysis, including mRNA, microRNA (miRNA), and transfer RNA fragments (tRFs), to characterize the transcriptional profiles in undifferentiated and differentiated HUPEC with APOL1 HR (G1/G2, 2 cell lines) and APOL1 low-risk (LR) (G0/G0, 2 cell lines) genotypes. We reanalyzed single-cell RNA-seq data from urinary podocytes from focal segmental glomerulosclerosis (FSGS) subjects to characterize the effect of APOL1 genotypes on podocyte transcriptomes. Differential expression analysis showed that the ribosomal pathway was one of the most enriched pathways, suggesting that altered function of the translation initiation machinery may contribute to APOL1 variant-induced podocyte injury. Expression of genes related to the elongation initiation factor 2 pathway was also enriched in the APOL1 HR urinary podocytes from single-cell RNA-seq, supporting a prior report on the role of this pathway in APOL1-associated cell injury. Expression of microRNA and tRFs were analyzed, and the profile of small RNAs differed by both differentiation status and APOL1 genotype. We have profiled the transcriptomic landscape of human podocytes, including mRNA, miRNA, and tRF, to characterize the effects of differentiation and of different APOL1 genotypes. The candidate pathways, miRNAs, and tRFs described here expand understanding of APOL1-associated podocytopathies.

Apolipoprotein L1 Genotypes and the Association of Urinary Potassium Excretion with CKD Progression.

Progressive CKD in Black individuals is strongly associated with polymorphisms in the APOL1 gene, but it is unknown whether dietary risk factors for CKD progression vary in high- versus low-risk APOL1 genotypes. We investigated if APOL1 genotypes modify associations of dietary potassium and sodium with CKD progression and death. We analyzed 1399 self-identified Black participants enrolled in the Chronic Renal Insufficiency Cohort from April 2003 to September 2008. Exposures were calibrated 24-hour urine potassium and sodium excretion. The primary outcome was CKD progression defined as the time to 50% decline in eGFR or kidney failure. The secondary outcome was CKD progression or death. We tested for an interaction between urinary potassium and sodium excretion and APOL1 genotypes. Median 24-hour urinary sodium and potassium excretions in Black participants were 150 mmol (interquartile range, 118-188) and 43 mmol (interquartile range, 35-54), respectively. Individuals with high- and low-risk APOL1 genotypes numbered 276 (20%) and 1104 (79%), respectively. After a median follow-up of 5.23 years, CKD progression events equaled 605, and after 7.29 years, CKD progression and death events equaled 868. There was significant interaction between APOL1 genotypes and urinary potassium excretion with CKD progression and CKD progression or death (P=0.003 and P=0.03, respectively). In those with high-risk APOL1 genotypes, higher urinary potassium excretion was associated with a lower risk of CKD progression (quartiles 2-4 versus 1: hazard ratio, 0.83; 95% confidence interval, 0.50 to 1.39; hazard ratio, 0.54; 95% confidence interval, 0.31 to 0.93; and hazard ratio, 0.50; 95% confidence interval, 0.27 to 0.93, respectively). In the low-risk APOL1 genotypes, higher urinary potassium excretion was associated with a higher risk of CKD progression (quartiles 2-4 versus 1: hazard ratio, 1.01; 95% confidence interval, 0.75 to 1.36; hazard ratio, 1.23; 95% confidence interval, 0.91 to 1.66; and hazard ratio, 1.53; 95% confidence interval, 1.12 to 2.09, respectively). We found no interaction between APOL1 genotypes and urinary sodium excretion with CKD outcomes. Higher urinary potassium excretion was associated with lower versus higher risk of CKD progression in APOL1 high-risk and low-risk genotypes, respectively.