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 A Meoni, Michael J Klag, Lingyi Lu, Pamela J Hicks, Carl D Langefeld, Rulan S Parekh, Donald W Bowden, Barry I Freedman, Family Investigation of Nephropathy and Diabetes (FIND) Research Group, S K Iyengar, R C Elston, K A B Goddard, J M Olson, S Ialacci, J Fondran, A Horvath, R Igo Jr, G Jun, K Kramp, J Molineros, S R E Quade, J R Sedor, J Schelling, A Pickens, L Humbert, L Getz-Fradley, S Adler, E Ipp, M Pahl, M F Seldin, S Snyder, J Tayek, E Hernandez, J LaPage, C Garcia, J Gonzalez, M Aguilar, M Klag, R Parekh, L Kao, L Meoni, T Whitehead, J Chester, W C Knowler, R L Hanson, R G Nelson, J Wolford, L Jones, R Juan, R Lovelace, C Luethe, L M Phillips, J Sewemaenewa, I Sili, B Waseta, M F Saad, S B Nicholas, Y-D I Chen, X Guo, J Rotter, K Taylor, M Budgett, F Hariri, P Zager, V Shah, M Scavini, A Bobelu, H Abboud, N Arar, R Duggirala, B S Kasinath, F Thameem, M Stern, B I Freedman, D W Bowden, C D Langefeld, S C Satko, S S Rich, S Warren, S Viverette, G Brooks, R Young, M Spainhour, C Winkler, M W Smith, M Thompson, R Hanson, B Kessing, D J Leehey, G Barone, D Thornley-Brown, C Jefferson, O F Kohn, C S Brown, J P Briggs, P L Kimmel, R Rasooly, D Warnock, L Cardon, R Chakraborty, G M Dunston, T Hostetter, S J O'Brien, J Rioux, R Spielman, 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 A Meoni, Michael J Klag, Lingyi Lu, Pamela J Hicks, Carl D Langefeld, Rulan S Parekh, Donald W Bowden, Barry I Freedman, Family Investigation of Nephropathy and Diabetes (FIND) Research Group, S K Iyengar, R C Elston, K A B Goddard, J M Olson, S Ialacci, J Fondran, A Horvath, R Igo Jr, G Jun, K Kramp, J Molineros, S R E Quade, J R Sedor, J Schelling, A Pickens, L Humbert, L Getz-Fradley, S Adler, E Ipp, M Pahl, M F Seldin, S Snyder, J Tayek, E Hernandez, J LaPage, C Garcia, J Gonzalez, M Aguilar, M Klag, R Parekh, L Kao, L Meoni, T Whitehead, J Chester, W C Knowler, R L Hanson, R G Nelson, J Wolford, L Jones, R Juan, R Lovelace, C Luethe, L M Phillips, J Sewemaenewa, I Sili, B Waseta, M F Saad, S B Nicholas, Y-D I Chen, X Guo, J Rotter, K Taylor, M Budgett, F Hariri, P Zager, V Shah, M Scavini, A Bobelu, H Abboud, N Arar, R Duggirala, B S Kasinath, F Thameem, M Stern, B I Freedman, D W Bowden, C D Langefeld, S C Satko, S S Rich, S Warren, S Viverette, G Brooks, R Young, M Spainhour, C Winkler, M W Smith, M Thompson, R Hanson, B Kessing, D J Leehey, G Barone, D Thornley-Brown, C Jefferson, O F Kohn, C S Brown, J P Briggs, P L Kimmel, R Rasooly, D Warnock, L Cardon, R Chakraborty, G M Dunston, T Hostetter, S J O'Brien, J Rioux, R Spielman
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.
Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Source: PubMed