BACKGROUND: Two APOL1 nephropathy variants confer substantial risk for non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs). Since not all genetically high-risk individuals develop ESKD, modifying factors likely contribute. Forty-two potentially interactive single nucleotide polymorphisms (SNPs) from a genome-wide association study in non-diabetic ESKD were tested for interaction with APOL1 to identify genes modifying risk for non-diabetic nephropathy. METHODS: SNPs were examined in an expanded sample of 1367 AA non-diabetic ESKD cases and 1504 AA non-nephropathy controls, with validation in an independent family-based cohort containing 608 first-degree relatives of index cases with non-diabetic ESKD. Logistic regression and mixed models were fitted to test for interaction effects with APOL1 on ESKD, estimated kidney function and albuminuria. RESULTS: Among ESKD samples, 14 of 42 SNPs demonstrated suggestive APOL1 interaction with P-values <0.05. After Bonferroni correction, significant interactions with APOL1 were seen with SNPs in podocin (rs16854341; NPHS2, P = 8.0 × 10(-4)), in SDCCAG8 (rs2802723; P = 5.0 × 10(-4)) and near BMP4 (rs8014363; P = 1.0 × 10(-3)); with trends for ENOX1 (rs9533534; P = 2.2 × 10(-3)) and near TRIB1 (rs4457349; P = 5.7 × 10(-3)). The minor allele in NPHS2 markedly changed the APOL1-ESKD association odds ratio (OR) from 7.03 to 1.76 (∼50% reduction in effect per copy of the minor allele), rs2802723 changed the OR from 5.1 to 10.5, and rs8014363 increased the OR from 4.8 to 9.5. NPHS2 (P = 0.05) and SDCCAG8 (P = 0.03) SNPs demonstrated APOL1 interaction with albuminuria in independent family-based samples. CONCLUSIONS: Variants in NPHS2, SDCCAG8 and near BMP4 appear to interact with APOL1 to modulate the risk for non-diabetic ESKD in AAs.
BACKGROUND: Two APOL1 nephropathy variants confer substantial risk for non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs). Since not all genetically high-risk individuals develop ESKD, modifying factors likely contribute. Forty-two potentially interactive single nucleotide polymorphisms (SNPs) from a genome-wide association study in non-diabetic ESKD were tested for interaction with APOL1 to identify genes modifying risk for non-diabetic nephropathy. METHODS: SNPs were examined in an expanded sample of 1367 AA non-diabetic ESKD cases and 1504 AA non-nephropathy controls, with validation in an independent family-based cohort containing 608 first-degree relatives of index cases with non-diabetic ESKD. Logistic regression and mixed models were fitted to test for interaction effects with APOL1 on ESKD, estimated kidney function and albuminuria. RESULTS: Among ESKD samples, 14 of 42 SNPs demonstrated suggestive APOL1 interaction with P-values <0.05. After Bonferroni correction, significant interactions with APOL1 were seen with SNPs in podocin (rs16854341; NPHS2, P = 8.0 × 10(-4)), in SDCCAG8 (rs2802723; P = 5.0 × 10(-4)) and near BMP4 (rs8014363; P = 1.0 × 10(-3)); with trends for ENOX1 (rs9533534; P = 2.2 × 10(-3)) and near TRIB1 (rs4457349; P = 5.7 × 10(-3)). The minor allele in NPHS2 markedly changed the APOL1-ESKD association odds ratio (OR) from 7.03 to 1.76 (∼50% reduction in effect per copy of the minor allele), rs2802723 changed the OR from 5.1 to 10.5, and rs8014363 increased the OR from 4.8 to 9.5. NPHS2 (P = 0.05) and SDCCAG8 (P = 0.03) SNPs demonstrated APOL1 interaction with albuminuria in independent family-based samples. CONCLUSIONS: Variants in NPHS2, SDCCAG8 and near BMP4 appear to interact with APOL1 to modulate the risk for non-diabetic ESKD in AAs.
Entities:
Keywords:
APOL1; African American; bone morphogenetic protein 4 (BMP4); kidney disease; podocin (NPHS2); serologically defined colon cancer antigen 8 (SDCCAG8)
Authors: Gianluca Caridi; Roberta Bertelli; Francesco Scolari; Simone Sanna-Cherchi; Marco Di Duca; Gian Marco Ghiggeri Journal: Kidney Int Date: 2003-07 Impact factor: 10.612
Authors: Stephanie M Karle; Barbara Uetz; Vera Ronner; Lisa Glaeser; Friedhelm Hildebrandt; Arno Fuchshuber Journal: J Am Soc Nephrol Date: 2002-02 Impact factor: 10.121
Authors: N Boute; O Gribouval; S Roselli; F Benessy; H Lee; A Fuchshuber; K Dahan; M C Gubler; P Niaudet; C Antignac Journal: Nat Genet Date: 2000-04 Impact factor: 38.330
Authors: K Schwarz; M Simons; J Reiser; M A Saleem; C Faul; W Kriz; A S Shaw; L B Holzman; P Mundel Journal: J Clin Invest Date: 2001-12 Impact factor: 14.808
Authors: Jasmin Divers; Marina Núñez; Kevin P High; Mariana Murea; Michael V Rocco; Lijun Ma; Donald W Bowden; Pamela J Hicks; Mitzie Spainhour; David A Ornelles; Steven B Kleiboeker; Kara Duncan; Carl D Langefeld; Jolyn Turner; Barry I Freedman Journal: Kidney Int Date: 2013-05-15 Impact factor: 10.612
Authors: Alexandre C Pereira; Aparecido B Pereira; Glória F Mota; Roberto S Cunha; Fernando L Herkenhoff; Martin R Pollak; José G Mill; José E Krieger Journal: Kidney Int Date: 2004-03 Impact factor: 10.612
Authors: Gianluca Caridi; Afig Berdeli; Monica Dagnino; Marco Di Duca; Sevgi Mir; Alphan Cura; Roberto Ravazzolo; Gian Marco Ghiggeri Journal: Am J Kidney Dis Date: 2004-04 Impact factor: 8.860
Authors: Hanghang Wang; Patrick H Pun; Lydia Kwee; Damian Craig; Carol Haynes; Megan Chryst-Ladd; Laura P Svetkey; Uptal D Patel; Elizabeth R Hauser; Martin R Pollak; William E Kraus; Svati H Shah Journal: Cardiorenal Med Date: 2016-12-29 Impact factor: 2.041
Authors: Carl D Langefeld; Mary E Comeau; Maggie C Y Ng; Meijian Guan; Latchezar Dimitrov; Poorva Mudgal; Mitzie H Spainhour; Bruce A Julian; Jeffrey C Edberg; Jennifer A Croker; Jasmin Divers; Pamela J Hicks; Donald W Bowden; Gary C Chan; Lijun Ma; Nicholette D Palmer; Robert P Kimberly; Barry I Freedman Journal: Kidney Int Date: 2018-06-07 Impact factor: 10.612
Authors: Morgan E Grams; Casey M Rebholz; Yuan Chen; Andreea M Rawlings; Michelle M Estrella; Elizabeth Selvin; Lawrence J Appel; Adrienne Tin; Josef Coresh Journal: J Am Soc Nephrol Date: 2016-03-10 Impact factor: 10.121
Authors: Teresa K Chen; Michael J Choi; W H Linda Kao; Brad C Astor; Julia J Scialla; Lawrence J Appel; Liang Li; Michael S Lipkowitz; Myles Wolf; Rulan S Parekh; Cheryl A Winkler; Michelle M Estrella; Deidra C Crews Journal: Clin J Am Soc Nephrol Date: 2015-10-01 Impact factor: 8.237
Authors: Atanu K Khatua; Amber M Cheatham; Etty D Kruzel; Pravin C Singhal; Karl Skorecki; Waldemar Popik Journal: Am J Physiol Cell Physiol Date: 2015-04-29 Impact factor: 4.249