Genetic Association and Gene-Gene Interaction Analyses in African American Dialysis Patients With Nondiabetic Nephropathy

Authors

• Meredith A. Bostrom, Wake Forest University
• W. H. Linda Kao, Johns Hopkins University
• Man Li, Johns Hopkins University
• Hanna E. Abboud, University of Texas - San Antonio
• Sharon G. Adler, University of California - Los Angeles
• Sudha K. Iyengar, Case Western University
• Paul L. Kimmel, National Institute of Diabetes and Digestive and Kidney Diseases
• Robert L. Hanson, National Institute of Diabetes and Digestive and Kidney Diseases
• Susanne B. Nicholas, University of California - Los Angeles
• Rebekah S. Rasooly, National Institute of Diabetes and Digestive and Kidney Diseases
• John R. Sedor, Case Western University
• Josef Coresh, Johns Hopkins University
• Orly F. Kohn, University of Chicago
• David J. Leehey, Loyal University
• Denyse Thornley-Brown, University of Alabama - Birmingham
• Erwin P. Bottinger, Mount Sinai School of Medicine
• Michael S. Lipkowitz, Georgetown University
• Lucy A. Meoni, Johns Hopkins University
• Michael J. Klag, Johns Hopkins University
• Lingyi Lu, Wake Forest University
• Pamela J. Hicks, Wake Forest University
• Carl D. Langefeld, Wake Forest University
• Rulan S. Parekh, Johns Hopkins University; University of Toronto - Canada
• Donald W. Bowden, Wake Forest University
• Barry I. Freedman, Wake Forest University
• Stephen J. O'Brien, Family Investigation of Nephropathy and Diabetes (FIND) Research GroupFollow
• Family Investigation of Nephropathy and Diabetes (FIND) Research Group

ORCID

0000-0001-7353-8301

ResearcherID

N-1726-2015

Document Type

Article

Publication Title

American Journal of Kidney Diseases

ISSN

0272-6386

Publication Date

2-1-2012

Keywords

African American, APOL1, CFH, End-stage renal disease, Family Investigation of Nephropathy and Diabetes (FIND), Focal segmental glomerulosclerosis (FSGS), Hypertension

Abstract

Background

African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans.

Study Design

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.

Predictors

Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes.

Outcomes

APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1 .

Results

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).

Limitations

Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy.

Conclusions

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.

Volume

59

Issue

2

First Page

210

Last Page

221

Comments

© 2012 by the National Kidney Foundation, Inc.

Additional Comments

National Institutes of Health grant #s: R01 DK 070941, R01 DK 084149, R01 DK53591, N01-HG-65403; National Institute of Diabetes and Digestive and Kidney Diseases grant #: F32 DK080617; FIND grant #s: U01DK57292, U01DK57329, U01DK057300, U01DK057298, U01DK057249, U01DK57295, U01DK070657, U01DK057303, U01DK070657, U01DK57304; CHOICE study #: DK07024; National Cancer Institute contract #: N01-CO-12400; National Center for Research Resources for the General Clinical Research Center grant #s: M01-RR-000080, M01-RR-07122, M01-RR-00425, M01-RR-00827-29, HSC M01-RR-00997, M01-RR-01346; Agency for Healthcare Research and Quality grant#: HS08365; National Heart, Lung, and Blood Institute grant #: HL62985

NSUWorks Citation

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