APOL1 Renal Risk Variants and Sickle Cell Trait Associations With Reduced Kidney Function in a Large Congolese Population-Based Study.

Introduction: APOL1, GSTM1 risk variants, and sickle cell trait (SCT) are associated with chronic kidney disease (CKD) among African Americans (AAs). Nevertheless, such evidence remains scarce in sub-Saharan Africa (SSA) populations. Methods: In a cross-sectional study, we evaluated the prevalence of these risk variants and their association with estimated glomerular filtration rate (eGFR), albuminuria, and CKD in urban (n = 587) and rural (n = 730) adults from South-Kivu, DR Congo (DRC). Furthermore, we evaluated APOL1 recessive model (high risk [HR] vs. low risk [LR]), SCT carriage, and the active versus inactive GSTM1 genotypes. Results: The frequencies of the APOL1 G1 and G2 alleles were 8.7% and 9.1%, respectively, and 3.2% carried the HR genotype. SCT and GSTM1 null allele frequencies were 3.8% and 51.2%, respectively. APOL1 HR was associated with lower eGFR (P = 0.047, odds ratio [OR] = 4). Individuals with SCT exhibited lower eGFR (P = 0.018), higher albuminuria (P = 0.032), and 2.4× increased risk of CKD (P = 0.031). APOL1 HR and SCT were synergistically associated with lower eGFR (P interaction = 0.012). The GSTM1 null allele was not significantly associated with any renal outcomes. Conclusion: Our study highlighted the impact of APOL1 and SCT variants on poorer renal outcomes in the DRC and advocates for further genetic studies in SSA settings.

APOL1 Risk Variants and Subclinical Cardiovascular Disease in Incident Hemodialysis Patients.

INTRODUCTION: To better understand the impact of APOL1 risk variants in end-stage renal disease (ESRD) we evaluated associations of APOL1 risk variants with subclinical cardiovascular disease (CVD) and mortality among African Americans initiating hemodialysis and enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD cohort study. METHODS: We modeled associations of APOL1 risk status (high = 2; low = 0/1 risk alleles) with baseline subclinical CVD (left ventricular [LV] hypertrophy; LV mass; ejection fraction; coronary artery calcification [CAC]; pulse wave velocity [PWV]) using logistic and linear regression and all-cause or cardiovascular mortality using Cox models, adjusting for age, sex, and ancestry. In sensitivity analyses, we further adjusted for systolic blood pressure and Charlson Comorbidity Index. RESULTS: Of 267 African American participants successfully genotyped for APOL1, 27% were high-risk carriers, 41% were women, and mean age was 53 years. At baseline, APOL1 high- versus low-risk status was independently associated with 50% and 53% lower odds of LV hypertrophy and CAC, respectively, and 10.7% lower LV mass. These associations were robust to further adjustment for comorbidities but not systolic blood pressure. APOL1 risk status was not associated with all-cause or cardiovascular mortality (mean follow-up 2.5 years). CONCLUSION: Among African American patients with incident hemodialysis, APOL1 high-risk status was associated with better subclinical measures of CVD but not mortality.

Sequencing rare and common APOL1 coding variants to determine kidney disease risk.

A third of African Americans with sporadic focal segmental glomerulosclerosis (FSGS) or HIV-associated nephropathy (HIVAN) do not carry APOL1 renal risk genotypes. This raises the possibility that other APOL1 variants may contribute to kidney disease. To address this question, we sequenced all APOL1 exons in 1437 Americans of African and European descent, including 464 patients with biopsy-proven FSGS/HIVAN. Testing for association with 33 common and rare variants with FSGS/HIVAN revealed no association independent of strong recessive G1 and G2 effects. Seeking additional variants that might have been under selection by pathogens and could represent candidates for kidney disease risk, we also sequenced an additional 1112 individuals representing 53 global populations. Except for G1 and G2, none of the 7 common codon-altering variants showed evidence of selection or could restore lysis against trypanosomes causing human African trypanosomiasis. Thus, only APOL1 G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN in the US population. Hence, in most potential clinical or screening applications, our study suggests that sequencing APOL1 exons is unlikely to bring additional information compared to genotyping only APOL1 G1 and G2 risk alleles.