title: Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material. tchen39@jhmi.edu.
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Chen
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Brad C
authors.initials: BC
authors.lastname: Astor
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Scialla
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Appel
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lipkowitz
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Rulan S
authors.initials: RS
authors.lastname: Parekh
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Estrella
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Deidra C
authors.initials: DC
authors.lastname: Crews
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D003404:Creatinine / Q000097:blood; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy / Q000208:ethnology; D015994:Incidence; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity / Q000208:ethnology; D010641:Phenotype; D016016:Proportional Hazards Models; D065840:Protective Factors; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D012307:Risk Factors; D012959:Socioeconomic Factors; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D015854:Up-Regulation
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D015415:Biomarkers; D005819:Genetic Markers; D008075:Lipoproteins, HDL; D003404:Creatinine
keywords: 25-hydroxyvitamin D2; AASK (African American Study of Kidney Disease and Hypertension); African Americans; apolipoprotein L1; blood pressure; body mass index; chronic; chronic kidney disease; fibroblast growth factor 23; genotype kidney failure; hypertension