Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy
American Journal of Kidney Diseases
African American, APOL1, CFH, End-stage renal disease, Family Investigation of Nephropathy and Diabetes (FIND), Focal segmental glomerulosclerosis (FSGS), Hypertension
African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans.
Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.
Setting & Participants
Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls.
Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes.
APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1 .
The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10 −24 ) and rs136148 (OR, 0.54; additive; P = 1.1 × 10 −7 ) with replication in FIND ( P = 5.0 × 10 −21 and 1.9 × 10 −05 , respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10 −4 ). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene ( NPHS2 ; P = 0.0001).
Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy.
This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.
Bostrom, Meredith A.; W. H. Linda Kao; Man Li; Hanna E. Abboud; Sharon G. Adler; Sudha K. Iyengar; Paul L. Kimmel; Robert L. Hanson; Susanne B. Nicholas; Rebekah S. Rasooly; John R. Sedor; Josef Coresh; Orly F. Kohn; David J. Leehey; Denyse Thornley-Brown; Erwin P. Bottinger; Michael S. Lipkowitz; Lucy A. Meoni; Michael J. Klag; Lingyi Lu; Pamela J. Hicks; Carl D. Langefeld; Rulan S. Parekh; Donald W. Bowden; Barry I. Freedman; Stephen J. O'Brien; and Family Investigation of Nephropathy and Diabetes (FIND) Research Group. 2012. "Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy." American Journal of Kidney Diseases 59, (2): 210-221. https://nsuworks.nova.edu/cnso_bio_facarticles/429