Biology Faculty Articles

Title

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

Document Type

Article

Publication Date

2-1-2012

Publication Title

American Journal of Kidney Diseases

Keywords

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

ISSN

0272-6386

Volume

59

Issue/No.

2

First Page

210

Last Page

221

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.

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

ORCID ID

0000-0001-7353-8301

ResearcherID

N-1726-2015

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