Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans

Genovese, Giulio; Friedman, David J.; Ross, Michael D.; Lecordier, Laurence; Uzureau, Pierrick; Freedman, Barry I.; Bowden, Donald W.; Langefeld, Carl D.; Oleksyk, Tarás K.; Knob, Andrea L. Uscinski; Bernhardy, Andrea J.; Hicks, Pamela J.; Nelson, George W.; Vanhollebeke, Benoît; Winkler, Cheryl A.; Kopp, Jeffrey B.; Pays, Étienne; Pollak, Martin R.

doi:10.1126/science.1193032

Cited by 1,780 publications

(2,160 citation statements)

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“…Consistent with prior studies, G1 (risk allele for rs73885319 and rs60910145) is comprised of 2 missense mutations (S342G and I384M) and G2 (risk allele for rs71785313) is characterized by a 6 base pair deletion (del N388/Y389) 4, 5. We used a recessive genetic model, defining the APOL1 high‐risk genotypes as having 2 risk alleles (G1/G1, G1/G2, or G2/G2) and the low‐risk genotypes as having 1 or no risk alleles (G1/G0, G2/G0, G0/G0).…”

Section: Methodssupporting

confidence: 84%

“…The APOL1 risk variants (rs73885319 and rs71785313) were genotyped using TaqMan assays (Applied Biosystems 7900) and DNA samples (extracted from buffy coat) collected at the baseline examination 4, 5, 30. Consistent with prior studies, G1 (risk allele for rs73885319 and rs60910145) is comprised of 2 missense mutations (S342G and I384M) and G2 (risk allele for rs71785313) is characterized by a 6 base pair deletion (del N388/Y389) 4, 5.…”

Section: Methodsmentioning

confidence: 99%

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Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

Chen

Katz

Estrella

et al. 2017

JAHA

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Background APOL1 genetic variants confer an increased risk for kidney disease. Their associations with cardiovascular disease (CVD) are less certain. We aimed to compare the prevalence of subclinical CVD and incidence of atherosclerotic CVD and heart failure by APOL1 genotypes among self‐identified black participants of MESA (Multi‐Ethnic Study of Atherosclerosis).Methods and ResultsCross‐sectional associations of APOL1 genotypes (high‐risk=2 alleles; low‐risk=0 or 1 allele) with coronary artery calcification, carotid‐intimal media thickness, and left ventricular mass were evaluated using logistic and linear regression. Longitudinal associations of APOL1 genotypes with incident myocardial infarction, stroke, coronary heart disease, and congestive heart failure were examined using Cox regression. We adjusted for African ancestry, age, and sex. We also evaluated whether hypertension or kidney function markers explained the observed associations. Among 1746 participants with APOL1 genotyping (mean age 62 years, 55% women, mean cystatin C–based estimated glomerular filtration rate 89 mL/min per 1.73 m2, 12% with albuminuria), 12% had the high‐risk genotypes. We found no difference in prevalence or severity of coronary artery calcification, carotid‐intimal media thickness, or left ventricular mass by APOL1 genotypes. The APOL1 high‐risk group was 82% more likely to develop incident heart failure compared with the low‐risk group (95% confidence interval, 1.01–3.28). Adjusting for hypertension (hazard ratio, 1.80; 95% confidence interval, 1.00–3.24) but not markers of kidney function (hazard ratio, 1.86; 95% confidence interval, 1.03–3.35) slightly attenuated this association. The APOL1 high‐risk genotypes were not significantly associated with other clinical CVD outcomes.ConclusionsAmong blacks without baseline CVD, the APOL1 high‐risk variants may be associated with increased risk for incident heart failure but not subclinical CVD or incident clinical atherosclerotic CVD.

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Section: Methodssupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

Chen

Katz

Estrella

et al. 2017

JAHA

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“…5 Mapping by admixture linkage disequilibrium studies revealed that variant alleles in the apolipoprotein L1 (APOL1) gene on chromosome 22 were strongly associated with an increased risk of renal disease among AAs. 6 Importantly, these APOL1 variants in the homozygous or compound heterozygous state increased the risk of hypertension-attributed ESRD and focal and segmental glomerulosclerosis by 10-to 17-fold and increased the risk of HIV-associated nephropathy by 29-fold. 6e8 The two APOL1 risk alleles are termed G1, which is a haplotype with two missense variants in near-complete linkage disequilibrium [c.(1072A>G; 1200T>G); p.(S342G; I384M); rs73885319 and rs60910145], and G2, which is an in-frame two amino acid deletion (c.1212_1217del6; p.Asn388_ Tyr389del; rs71785313).…”

mentioning

confidence: 99%

“…6e8 The two APOL1 risk alleles are termed G1, which is a haplotype with two missense variants in near-complete linkage disequilibrium [c.(1072A>G; 1200T>G); p.(S342G; I384M); rs73885319 and rs60910145], and G2, which is an in-frame two amino acid deletion (c.1212_1217del6; p.Asn388_ Tyr389del; rs71785313). 6,9 Carriers of two G1 or G2 alleles are at significantly increased risks for developing CKD and ESRD compared with both heterozygous G1 or G2 carriers and noncarriers. 6,10 The overall incidence rate of CKD has been reported to be approximately 12 events/1000 personyears and approximately 8 events/1000 person-years for AA individuals at high and low APOL1 genetic risk, respectively.…”

mentioning

confidence: 99%

“…6,9 Carriers of two G1 or G2 alleles are at significantly increased risks for developing CKD and ESRD compared with both heterozygous G1 or G2 carriers and noncarriers. 6,10 The overall incidence rate of CKD has been reported to be approximately 12 events/1000 personyears and approximately 8 events/1000 person-years for AA individuals at high and low APOL1 genetic risk, respectively. 10 Absolute risks for progression to ESRD among AA individuals with CKD have been reported to be 58% and 37% for those at high and low APOL1 genetic risk, respectively.…”

mentioning

confidence: 99%

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Analytical Validation of a Personalized Medicine APOL1 Genotyping Assay for Nondiabetic Chronic Kidney Disease Risk Assessment

Zhang

Fedick

Wasserman

et al. 2016

The Journal of Molecular Diagnostics

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The incidence of chronic kidney disease (CKD) varies by ancestry, with African Americans (AA) having a threefold to fourfold higher rate than whites. Notably, two APOL1 alleles, termed G1 [c.(1072A>G; 1200T>G)] and G2 (c.1212_1217del6), are strongly associated with higher rates of nondiabetic CKD and an increased risk for hypertensive end-stage renal disease. This has prompted the opportunity to implement APOL1 testing to identify at-risk patients and modify other risk factors to reduce the progression of CKD to end-stage renal disease. We developed an APOL1 genotyping assay using multiplex allele-specific primer extension, and validated using 58 positive and negative controls. Genotyping results were completely concordant with Sanger sequencing, and both triplicate interrun and intrarun genotyping results were completely concordant. Multiethnic APOL1 allele frequencies were also determined by genotyping 7059 AA, Hispanic, and Asian individuals from the New York City metropolitan area. The AA, Hispanic, and Asian APOL1 G1 and G2 allele frequencies were 0.22 and 0.13, 0.037 and 0.025, and 0.013 and 0.004, respectively. Notably, approximately 14% of the AA population carried two risk alleles and are at increased risk for CKD, compared with <1% of the Hispanic and Asian populations. This novel APOL1 genotyping assay is robust and highly accurate, and represents one of the first personalized medicine clinical genetic tests for disease risk prediction. (J Mol Diagn 2016, 18: 260e266; http://dx.doi.org/10.1016/j.jmoldx.2015 Chronic kidney disease (CKD) is a progressive loss of renal function that can be defined by laboratory findings, such as pathological abnormalities, composition of blood or urine, and decreased glomerular filtration rates. 1 CKD is classified into five different stages according to the presence or absence of kidney damage and the level of kidney function, and its symptoms include hypertension, anemia, hyperkalemia, metabolic acidosis, and bone disease.

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Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans

Naik

Derebail

Grams

et al. 2014

JAMA

175

192

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IMPORTANCE The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain. OBJECTIVE To describe the relationship between SCT and CKD and albuminuria in self-identified African Americans. DESIGN, SETTING, AND PARTICIPANTS Using 5 large, prospective, US population-based studies (the Atherosclerosis Risk in Communities Study [ARIC, 1987–2013; n = 3402], Jackson Heart Study [JHS, 2000–2012; n = 2105], Coronary Artery Risk Development in Young Adults [CARDIA, 1985–2006; n = 848], Multi-Ethnic Study of Atherosclerosis [MESA, 2000–2012; n = 1620], and Women’s Health Initiative [WHI, 1993–2012; n = 8000]), we evaluated 15 975 self-identified African Americans (1248 participants with SCT [SCT carriers] and 14 727 participants without SCT [noncarriers]). MAIN OUTCOMES AND MEASURES Primary outcomes were CKD (defined as an estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2 at baseline or follow-up), incident CKD, albuminuria (defined as a spot urine albumin:creatinine ratio of >30 mg/g or albumin excretion rate >30 mg/24 hours), and decline in eGFR (defined as a decrease of >3 mL/min/1.73 m2 per year). Effect sizes were calculated separately for each cohort and were subsequently meta-analyzed using a random-effects model. RESULTS A total of 2233 individuals (239 of 1247 SCT carriers [19.2%] vs 1994 of 14 722 noncarriers [13.5%]) had CKD, 1298 (140 of 675 SCT carriers [20.7%] vs 1158 of 8481 noncarriers [13.7%]) experienced incident CKD, 1719 (150 of 665 SCT carriers [22.6%] vs 1569 of 8249 noncarriers [19.0%]) experienced decline in eGFR, and 1322 (154 of 485 SCT carriers [31.8%] vs 1168 of 5947 noncarriers [19.6%]) had albuminuria during the study period. Individuals with SCT had an increased risk of CKD (odds ratio [OR], 1.57 [95% CI, 1.34–1.84]; absolute risk difference [ARD], 7.6% [95% CI, 4.7%–10.8%]), incident CKD (OR, 1.79 [95% CI, 1.45–2.20]; ARD, 8.5% [95% CI, 5.1%–12.3%]), and decline in eGFR (OR, 1.32 [95% CI, 1.07–1.61]; ARD, 6.1% [95% CI, 1.4%–13.0%]) compared with noncarriers. Sickle cell trait was also associated with albuminuria (OR, 1.86 [95% CI, 1.49–2.31]; ARD, 12.6% [95% CI, 7.7%–17.7%]). CONCLUSIONS AND RELEVANCE Among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers. These findings suggest that SCT may be associated with the higher risk of kidney disease in African Americans.

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Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans

Cited by 1,780 publications

References 25 publications

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

Association Between APOL1 Genotypes and Risk of Cardiovascular Disease in MESA (Multi‐Ethnic Study of Atherosclerosis)

Analytical Validation of a Personalized Medicine APOL1 Genotyping Assay for Nondiabetic Chronic Kidney Disease Risk Assessment

Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans

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