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

Abstract

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.

• Authors: Teresa K Chen, Michael J Choi, W H Linda Kao, Brad C Astor, Julia J Scialla, Lawrence J Appel, Liang Li, Michael S Lipkowitz, Myles Wolf, Rulan S Parekh, Cheryl A Winkler, Michelle M Estrella, Deidra C Crews
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 10 Issue 12 Pg. 2128-35 (Dec 07 2015) ISSN: 1555-905X [Electronic] United States
• PMID: 26430087 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American Society of Nephrology.

Chemical References

• APOL1 protein, human
• Apolipoprotein L1
• Apolipoproteins
• Biomarkers
• Genetic Markers
• Lipoproteins, HDL
• Creatinine

Topics

• Adult
• Black or African American (genetics)
• Apolipoprotein L1
• Apolipoproteins (genetics)
• Biomarkers (blood)
• Creatinine (blood)
• Disease Progression
• Female
• Gene Frequency
• Gene-Environment Interaction
• Genetic Association Studies
• Genetic Markers
• Genetic Predisposition to Disease
• Humans
• Hypertension (diagnosis, drug therapy, ethnology)
• Incidence
• Kidney Failure, Chronic (diagnosis, ethnology, genetics)
• Lipoproteins, HDL (genetics)
• Male
• Middle Aged
• Multivariate Analysis
• Obesity (ethnology)
• Phenotype
• Proportional Hazards Models
• Protective Factors
• Renal Insufficiency, Chronic (blood, diagnosis, ethnology, genetics)
• Risk Factors
• Socioeconomic Factors
• Time Factors
• United States (epidemiology)
• Up-Regulation