APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease

Abstract

BACKGROUND Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression

“…The AASK study initially began as a trial (1,(14)(15)(16). From 1995 to 2001, 1094 African Americans with CKD attributed to hypertension were randomized to a mean arterial BP goal of #92 (intensive control group) or 102-107 mmHg (standard control group).…”

“…These findings suggest that APOL1 risk variants partially account for the excess burden of ESRD observed in African Americans (1,4,7); however, not all individuals with the APOL1 highrisk genotype develop ESRD or even CKD (1,4).…”

“…In recent years, genetic variants encoding apolipoprotein L1 (APOL1) have emerged as a risk factor for ESRD among African Americans (1)(2)(3)(4). The presence of two APOL1 risk variants (G1 and G2) on chromosome 22 confers protection against the parasite Trypanosoma brucei rhodesiense; the same genetic variants have also been associated with increased risk for various forms of kidney disease.…”

“…In the African American Study of Kidney Disease and Hypertension (AASK) and the Chronic Renal Insufficiency Cohort, Parsa et al (1) showed that individuals with two APOL1 risk alleles (high-risk genotype) were more likely to experience CKD progression than those with one or no copies (lowrisk genotypes). These findings suggest that APOL1 risk variants partially account for the excess burden of ESRD observed in African Americans (1,4,7); however, not all individuals with the APOL1 highrisk genotype develop ESRD or even CKD (1,4).…”

How the genomics revolution could finally help Africa

“…Nephrologist Dwomoa Adu at the University of Ghana Medical School in Accra, one of the principal investigators in the H3Africa Kidney Research Network, says there are no known environmental factors that explain this. But many Africans carry variants in the gene for apolipoprotein L1 (APOL1) that seem to confer an increased risk of developing kidney disease 3 . These variants have probably flourished in Africa because they confer resistance to trypanosomiasis, or sleeping sickness, a parasitic disease transmitted by the tsetse fly.…”