Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

Freedman, Barry I.; Skorecki, Karl

doi:10.2215/cjn.01330214

Cited by 100 publications

(90 citation statements)

References 72 publications

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“…36 Having carried out our study in a high HIV prevalence setting, with predominantly HIV-1 subtype C, puts HIV as an important environmental factor inducing APOL1-mediated kidney disease, supporting a two-hit model for APOL1-associated disease expression. 37 This study highlights the need to consider gene-environment interaction in the interpretation of genome-wide association studies for other common diseases.…”

Section: Discussionmentioning

confidence: 94%

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

288

265

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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: 94%

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

288

265

View full text Add to dashboard Cite

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“…Additional genetic and/or nongenetic factors seem to modify the risk of kidney disease progression in individuals with the high-risk APOL1 genotype (8). One such example is HIVAN.…”

Section: Introductionmentioning

confidence: 99%

“…Although individuals with two APOL1 high-risk alleles have a 4.25% lifetime risk of developing FSGS, those additionally infected with HIV have a 50% lifetime risk of developing HIVAN (6). Moreover, control of HIV infection with highly active antiretroviral therapy reduces the risk of CKD in patients with the APOL1 high-risk genotype (8)(9)(10). In another example, Divers et al (11) reported that the presence of JC viruria may be protective against kidney disease among individuals with two APOL1 high-risk alleles.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, Divers et al (13) have also described interactions between single-nucleotide polymorphisms in the podocin (NPHS2), serologically defined colon cancer antigen 8 (SDCCAG8), and (near) bone morphogenetic protein 4 (BMP4) genes and APOL1-associated ESRD. Thus, although APOL1 high-risk variants are associated with an increased risk for CKD, this risk may be augmented or reduced by certain genetic, environmental, or clinical factors yet to be fully elucidated (8).…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Choi²,

Kao³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications.Design, setting, participants, & measurements Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD).Results Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m 2 , and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index $30 versus ,30 kg/m 2 ; P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen $8 versus ,8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction .0.05 for each).Conclusions Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1-related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.

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“…The APOL1 high-risk genotype (two copies of the G1 or G2 alleles) has a population frequency of approximately 13% in African Americans and confers an approximately 2-fold higher risk for kidney function decline in cohort studies (8,9). Although the role of APOL1 in relation to kidney function is largely unknown, environmental factors probably affect APOL1-associated renal risk (10). For example, HIV infection (and particularly an unsuppressed viral load) in individuals with the APOL1 high-risk genotype appears to increase the susceptibility for progressive kidney disease (11,12).…”

Section: Introductionmentioning

confidence: 99%

Hemostatic Factors, APOL1 Risk Variants, and the Risk of ESRD in the Atherosclerosis Risk in Communities Study

Tin

Grams

Maruthur

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Hemostatic factors have been associated with kidney function decline, and evidence suggests stronger effects among African Americans. The presence of APOL1 renal risk variants, common in African Americans, might partly underlie this risk difference.Design, setting, participants, & measurements A total of 13,337 participants in the Atherosclerosis Risk in Communities study were followed from 1987-1989 until 2010. Participants were categorized into three groups by ancestry and APOL1 risk status: European Americans (n=10,206), African Americans with zero or one APOL1 risk allele (n=2,733), and African Americans with two APOL1 risk alleles (n=398). ESRD events were ascertained through linkage to the US Renal Data System. Cox regression was used to estimate the risk for ESRD associated with hemostatic factors (factor VIIc, factor VIIIc, fibrinogen, von Willebrand factor, protein C, and antithrombin III).Results There were 232 cases of ESRD over 21.5 years (European Americans, 119; African Americans with zero or one APOL1 risk allele, 94; African Americans with two APOL1 risk alleles, 19). In unadjusted and adjusted analysis of the overall population, higher levels of all hemostatic factors, except antithrombin III, were significantly associated with ESRD (all P,0.05). Factor VIIc had the strongest association (per one interquartile range; adjusted hazard ratio, 1.46; 95% confidence interval, 1.21 to 1.76). With the exception of fibrinogen, the risk associated with each hemostatic factor was stronger in African Americans with two APOL1 risk alleles compared with the other two groups. Statistically significant interactions were seen for factor VIIIc and protein C (interaction between those with two APOL1 risk allele and the other two groups: P,0.02 for factor VIIIc and ,0.04 for protein C).Conclusions Higher levels of factor VIIc, VIIIc, fibrinogen, von Willebrand factor, and protein C were associated with ESRD risk, with a significantly stronger association of factor VIIIc and protein C in African Americans with two APOL1 risk alleles.

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Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

Cited by 100 publications

References 72 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

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

Hemostatic Factors, APOL1 Risk Variants, and the Risk of ESRD in the Atherosclerosis Risk in Communities Study

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