Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy

Meredith A. Bostrom, 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 Ann Meoni, Michael John Klag, Lingyi Lu & 5 others Pamela J. Hicks, Carl D. Langefeld, Rulan S. Parekh, Donald W. Bowden, Barry I. Freedman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)210-221
Number of pages12
JournalAmerican Journal of Kidney Diseases
Volume59
Issue number2
DOIs
StatePublished - Feb 2012

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African Americans
Dialysis
Single Nucleotide Polymorphism
Genome-Wide Association Study
Genes
Meta-Analysis

Keywords

  • African American
  • APOL1
  • CFH
  • end-stage renal disease
  • Family Investigation of Nephropathy and Diabetes (FIND)
  • focal segmental glomerulosclerosis (FSGS)
  • hypertension

ASJC Scopus subject areas

  • Nephrology

Cite this

Bostrom, M. A., Kao, W. H. L., Li, M., Abboud, H. E., Adler, S. G., Iyengar, S. K., ... Freedman, B. I. (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://doi.org/10.1053/j.ajkd.2011.09.020

Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy. / Bostrom, Meredith A.; Kao, W. H Linda; Li, Man; Abboud, Hanna E.; Adler, Sharon G.; Iyengar, Sudha K.; Kimmel, Paul L.; Hanson, Robert L.; Nicholas, Susanne B.; Rasooly, Rebekah S.; Sedor, John R.; Coresh, Josef; Kohn, Orly F.; Leehey, David J.; Thornley-Brown, Denyse; Bottinger, Erwin P.; Lipkowitz, Michael S.; Meoni, Lucy Ann; Klag, Michael John; Lu, Lingyi; Hicks, Pamela J.; Langefeld, Carl D.; Parekh, Rulan S.; Bowden, Donald W.; Freedman, Barry I.

In: American Journal of Kidney Diseases, Vol. 59, No. 2, 02.2012, p. 210-221.

Research output: Contribution to journalArticle

Bostrom, MA, Kao, WHL, Li, M, Abboud, HE, Adler, SG, Iyengar, SK, Kimmel, PL, Hanson, RL, Nicholas, SB, Rasooly, RS, Sedor, JR, Coresh, J, Kohn, OF, Leehey, DJ, Thornley-Brown, D, Bottinger, EP, Lipkowitz, MS, Meoni, LA, Klag, MJ, Lu, L, Hicks, PJ, Langefeld, CD, Parekh, RS, Bowden, DW & Freedman, BI 2012, 'Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy', American Journal of Kidney Diseases, vol. 59, no. 2, pp. 210-221. https://doi.org/10.1053/j.ajkd.2011.09.020
Bostrom, Meredith A. ; Kao, W. H Linda ; Li, Man ; Abboud, Hanna E. ; Adler, Sharon G. ; Iyengar, Sudha K. ; Kimmel, Paul L. ; Hanson, Robert L. ; Nicholas, Susanne B. ; Rasooly, Rebekah S. ; Sedor, John R. ; Coresh, Josef ; Kohn, Orly F. ; Leehey, David J. ; Thornley-Brown, Denyse ; Bottinger, Erwin P. ; Lipkowitz, Michael S. ; Meoni, Lucy Ann ; Klag, Michael John ; Lu, Lingyi ; Hicks, Pamela J. ; Langefeld, Carl D. ; Parekh, Rulan S. ; Bowden, Donald W. ; Freedman, Barry I. / Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy. In: American Journal of Kidney Diseases. 2012 ; Vol. 59, No. 2. pp. 210-221.
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T1 - Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy

AU - Bostrom, Meredith A.

AU - Kao, W. H Linda

AU - Li, Man

AU - Abboud, Hanna E.

AU - Adler, Sharon G.

AU - Iyengar, Sudha K.

AU - Kimmel, Paul L.

AU - Hanson, Robert L.

AU - Nicholas, Susanne B.

AU - Rasooly, Rebekah S.

AU - Sedor, John R.

AU - Coresh, Josef

AU - Kohn, Orly F.

AU - Leehey, David J.

AU - Thornley-Brown, Denyse

AU - Bottinger, Erwin P.

AU - Lipkowitz, Michael S.

AU - Meoni, Lucy Ann

AU - Klag, Michael John

AU - Lu, Lingyi

AU - Hicks, Pamela J.

AU - Langefeld, Carl D.

AU - Parekh, Rulan S.

AU - Bowden, Donald W.

AU - Freedman, Barry I.

PY - 2012/2

Y1 - 2012/2

N2 - 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.

AB - 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.

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KW - APOL1

KW - CFH

KW - end-stage renal disease

KW - Family Investigation of Nephropathy and Diabetes (FIND)

KW - focal segmental glomerulosclerosis (FSGS)

KW - hypertension

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