APOL1 Kidney Risk Alleles: Population Genetics and Disease Associations

Limou, Sophie; Nelson, George W.; Kopp, Jeffrey B.; Winkler, Cheryl A.

doi:10.1053/j.ackd.2014.06.005

Cited by 179 publications

(206 citation statements)

References 43 publications

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“…The risk of developing HIVAN is substantial for individuals living with HIV infection and possessing two APOL1 risk alleles. 13,27 We also detected a rare, recombinant haplotype, G1 +M (A-G-I), in the heterozygous state (G1 GM /G1 +M ), in a single individual with HIV-positive CKD, which has not been previously reported in the 1000 Genomes Project or in previous studies of African populations, summarized by Thomson et al 33 and Limou et al 34 The molecular mechanisms by which APOL1 variants cause kidney disease remain unclear. This protein is expressed in podocytes and proximal tubular epithelial cells in normal kidneys and arteriolar endothelial cells and in vascular smooth muscle cells in HIVAN and FSGS biopsies.…”

Section: Discussionmentioning

confidence: 46%

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans

Kasembeli

Duarte

Ramsay

et al. 2015

Journal of the American Society of Nephrology

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289

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APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a SouthAfrican black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P,0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.

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Section: Discussionmentioning

confidence: 46%

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans

Kasembeli

Duarte

Ramsay

et al. 2015

Journal of the American Society of Nephrology

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289

265

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“…Among the 6814 participants, a total of 3217 (1746 black and 1471 Hispanic) were successfully genotyped for the APOL1 risk variants. The APOL1 risk variants are extremely rare in people of European descent 33, 34. We excluded individuals of Hispanic origin because of the relatively low prevalence of APOL1 risk variants in this ethnic group and the potential for confounding by ethnicity 35.…”

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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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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“…7,11,12 Persons of European ancestry are known to have extremely low frequencies of these variants. 17,18 Global ancestry was estimated using the software Eigenstrat. 19 Covariates Age, sex and race were ascertained by self-report using standardized questionnaires.…”

Section: Genotypingmentioning

confidence: 99%

APOL1 Genotype and Race Differences in Incident Albuminuria and Renal Function Decline

Peralta

Bibbins‐Domingo

Vittinghoff

et al. 2016

Journal of the American Society of Nephrology

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125

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Variants in the APOL1 gene are associated with kidney disease in blacks. We examined associations of APOL1 with incident albuminuria and kidney function decline among 3030 young adults with preserved GFR in the Coronary Artery Risk Development in Young Adults (CARDIA) study. eGFR by cystatin C (eGFRcys) and albumin-to-creatinine ratio were measured at scheduled examinations. Participants were white (n=1700), high-risk black (two APOL1 risk alleles, n=176), and low-risk black (zero/one risk allele, n=1154). Mean age was 35 years, mean eGFRcys was 107 ml/min per 1.73 m 2 , and 13.2% of blacks had two APOL1 alleles. The incidence rate per 1000 person-years (95% confidence interval) for albuminuria over 15 years was 15.6 (10.6-22.1) for high-risk blacks, 7.8 (6.4-9.4) for low-risk blacks, and 3.9 (3.1-4.8) for whites. Compared with whites, the odds ratio (95% confidence interval) for incident albuminuria was 5.71 (3.64-8.94) for high-risk blacks and 2.32 (1.73-3.13) for low-risk blacks. Adjustment for risk factors attenuated the difference between low-risk blacks and whites (odds ratio 1.21, 95% confidence interval 0.86-1.71). After adjustment, high-risk blacks had a 0.45% faster yearly eGFRcys decline over 9.3 years compared with whites. Low-risk blacks also had a faster yearly eGFRcys decline compared with whites, but this difference was attenuated after adjustment for risk factors and socioeconomic position. In conclusion, blacks with two APOL1 risk alleles had the highest risk for albuminuria and eGFRcys decline in young adulthood, whereas disparities between low-risk blacks and whites were related to differences in traditional risk factors.

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APOL1 Kidney Risk Alleles: Population Genetics and Disease Associations

Cited by 179 publications

References 43 publications

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans

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

APOL1 Genotype and Race Differences in Incident Albuminuria and Renal Function Decline

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