Abstract
African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P corr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P corr < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D-attributed ESKD in the AA population.
Similar content being viewed by others
References
1000 Genomes Project Consortium, Abecasis GR, Altshuler D et al (2010) A map of human genome variation from population-scale sequencing. Nature 467:1061–1073. doi:10.1038/nature09534
Abu Seman N, He B, Ojala JRM et al (2014) Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy. Am J Nephrol 40:408–416. doi:10.1159/000368916
Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249. doi:10.1038/nmeth0410-248
Akilesh S, Suleiman H, Yu H et al (2011) Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest 121:4127–4137. doi:10.1172/JCI46458
Alpert JS, Coffman JD, Balodimos MC et al (1972) Capillary permeability and blood flow in skeletal muscle of patients with diabetes mellitus and genetic prediabetes. N Engl J Med 286:454–460. doi:10.1056/NEJM197203022860903
Badal SS, Danesh FR (2014) New insights into molecular mechanisms of diabetic kidney disease. Am J Kidney Dis 63:S63–S83. doi:10.1053/j.ajkd.2013.10.047
Bonomo JA, Guan M, Ng MCY et al (2014a) The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease. Hum Mol Genet. doi:10.1093/hmg/ddu362
Bonomo JA, Ng MCY, Palmer ND et al (2014b) Coding variants in nephrin (NPHS1) and susceptibility to nephropathy in African Americans. Clin J Am Soc Nephrol CJASN 9:1434–1440. doi:10.2215/CJN.00290114
Brown D, Paunescu TG, Breton S, Marshansky V (2009) Regulation of the V-ATPase in kidney epithelial cells: dual role in acid-base homeostasis and vesicle trafficking. J Exp Biol 212:1762–1772. doi:10.1242/jeb.028803
Byrne C, Nedelman J, Luke RG (1994) Race, socioeconomic status, and the development of end-stage renal disease. Am J Kidney Dis Off J Natl Kidney Found 23:16–22
Cingolani P, Platts A, Wang LL et al (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff. Fly (Austin) 6:80–92. doi:10.4161/fly.19695
Davydov EV, Goode DL, Sirota M et al (2010) Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6:e1001025. doi:10.1371/journal.pcbi.1001025
Delaneau O, Marchini J, Zagury J-F (2012) A linear complexity phasing method for thousands of genomes. Nat Methods 9:179–181. doi:10.1038/nmeth.1785
Deshmukh HA, Palmer CNA, Morris AD, Colhoun HM (2013) Investigation of known estimated glomerular filtration rate loci in patients with type 2 diabetes. Diabet Med J Br Diabet Assoc 30:1230–1235. doi:10.1111/dme.12211
Erwin GD, Oksenberg N, Truty RM et al (2014) Integrating diverse datasets improves developmental enhancer prediction. PLoS Comput Biol 10:e1003677. doi:10.1371/journal.pcbi.1003677
Fan Q, Xing Y, Ding J et al (2006) The relationship among nephrin, podocin, CD2AP, and alpha-actinin might not be a true “interaction” in podocyte. Kidney Int 69:1207–1215. doi:10.1038/sj.ki.5000245
Freedman BI (2002) End-stage renal failure in African Americans: insights in kidney disease susceptibility. Nephrol Dial Transpl 17:198–200. doi:10.1093/ndt/17.2.198
Freedman BI, Tuttle AB, Spray BJ (1995) Familial predisposition to nephropathy in African-Americans with non-insulin-dependent diabetes mellitus. Am J Kidney Dis 25:710–713. doi:10.1016/0272-6386(95)90546-4
Freedman BI, Langefeld CD, Lu L et al (2011) Differential effects of MYH9 and APOL1 risk variants on FRMD3 association with diabetic ESRD in African Americans. PLoS Genet. doi:10.1371/journal.pgen.1002150
Gao X, Starmer J, Martin ER (2008) A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet Epidemiol 32:361–369. doi:10.1002/gepi.20310
Gaut JP, Hoshi M, Jain S, Liapis H (2014) Claudin-1 and Nephrin label cellular crescents in diabetic glomerulosclerosis. Hum Pathol 45:628–635. doi:10.1016/j.humpath.2013.10.030
Genovese G, Friedman DJ, Ross MD et al (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841–845. doi:10.1126/science.1193032
Girach A, Vignati L (2006) Diabetic microvascular complications—can the presence of one predict the development of another? J Diabetes Complicat 20:228–237. doi:10.1016/j.jdiacomp.2006.03.001
Heidet L, Arrondel C, Forestier L et al (2001) Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol JASN 12:97–106
Hou J, Renigunta A, Yang J, Waldegger S (2010) Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization. Proc Natl Acad Sci USA 107:18010–18015. doi:10.1073/pnas.1009399107
Hyvönen ME, Ihalmo P, Sandholm N et al (2013) CD2AP is associated with end-stage renal disease in patients with type 1 diabetes. Acta Diabetol 50:887–897. doi:10.1007/s00592-013-0475-9
Iyengar SK, Sedor JR, Freedman BI et al (2015) Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: Family Investigation of Nephropathy and Diabetes (FIND). PLoS Genet 11:e1005352. doi:10.1371/journal.pgen.1005352
Kashtan CE (1995) Clinical and molecular diagnosis of Alport syndrome. Proc Assoc Am Phys 107:306–313
Katoh M, Katoh M (2004) Identification and characterization of ARHGAP24 and ARHGAP25 genes in silico. Int J Mol Med 14:333–338
Kircher M, Witten DM, Jain P et al (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315. doi:10.1038/ng.2892
Kirsch KH, Georgescu MM, Ishimaru S, Hanafusa H (1999) CMS: an adapter molecule involved in cytoskeletal rearrangements. Proc Natl Acad Sci USA 96:6211–6216
Kiuchi-Saishin Y, Gotoh S, Furuse M et al (2002) Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol 13:875–886
Li WY, Huey CL, Yu ASL (2004) Expression of claudin-7 and -8 along the mouse nephron. Am J Physiol Ren Physiol 286:F1063–F1071. doi:10.1152/ajprenal.00384.2003
Liu DJ, Peloso GM, Zhan X et al (2014) Meta-analysis of gene-level tests for rare variant association. Nat Genet 46:200–204. doi:10.1038/ng.2852
Liu X, White S, Peng B et al (2016) WGSA: an annotation pipeline for human genome sequencing studies. J Med Genet 53:111–112. doi:10.1136/jmedgenet-2015-103423
Löwik MM, Groenen PJTA, Pronk I et al (2007) Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation. Kidney Int 72:1198–1203. doi:10.1038/sj.ki.5002469
Ma J, Guan M, Bowden DW et al (2016) Association analysis of the cubilin (CUBN) and megalin (LRP2) genes with ESRD in African Americans. Clin J Am Soc Nephrol 11:1034–1043. doi:10.2215/CJN.12971215
Madsen BE, Browning SR (2009) A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet 5:e1000384. doi:10.1371/journal.pgen.1000384
Maeda S (2004) Genome-wide search for susceptibility gene to diabetic nephropathy by gene-based SNP. Diabetes Res Clin Pract 66:S45–S47. doi:10.1016/j.diabres.2003.09.017
Marchini J, Howie B, Myers S et al (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39:906–913. doi:10.1038/ng2088
Mason RM, Wahab NA (2003) Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol 14:1358–1373. doi:10.1097/01.ASN.0000065640.77499.D7
McDonough CW, Palmer ND, Hicks PJ et al (2011) A genome wide association study for diabetic nephropathy genes in African Americans. Kidney Int 79:563–572. doi:10.1038/ki.2010.467
McLaren W, Pritchard B, Rios D et al (2010) Deriving the consequences of genomic variants with the Ensembl API and SNP effect predictor. Bioinformatics 26:2069–2070. doi:10.1093/bioinformatics/btq330
Miner JH (2011) Glomerular basement membrane composition and the filtration barrier. Pediatr Nephrol Berl Ger 26:1413–1417. doi:10.1007/s00467-011-1785-1
Molina-Jijón E, Rodríguez-Muñoz R, Namorado M, del C et al (2014) Oxidative stress induces claudin-2 nitration in experimental type 1 diabetic nephropathy. Free Radic Biol Med 72:162–175. doi:10.1016/j.freeradbiomed.2014.03.040
Olbrich H, Fliegauf M, Hoefele J et al (2003) Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Nat Genet 34:455–459. doi:10.1038/ng1216
Pezzolesi MG, Poznik GD, Mychaleckyj JC et al (2009) Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58:1403–1410. doi:10.2337/db08-1514
Pirinen M, Donnelly P, Spencer CCA (2013) Efficient computation with a linear mixed model on large-scale data sets with applications to genetic studies. Ann Appl Stat 7:369–390. doi:10.1214/12-AOAS586
Pollak MR (2014) Familial FSGS. Adv Chronic Kidney Dis 21:422–425. doi:10.1053/j.ackd.2014.06.001
Prete DD, Anglani F, Forino M et al (1997) Down-regulation of glomerular matrix metalloproteinase-2 gene in human NIDDM. Diabetologia 40:1449–1454. doi:10.1007/s001250050848
Prockop DJ (1992) Mutations in collagen genes as a cause of connective-tissue diseases. N Engl J Med 326:540–546. doi:10.1056/NEJM199202203260807
Pruitt KD, Brown GR, Hiatt SM et al (2014) RefSeq: an update on mammalian reference sequences. Nucleic Acids Res 42:D756–D763. doi:10.1093/nar/gkt1114
Quang D, Chen Y, Xie X (2015) DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics 31:761–763. doi:10.1093/bioinformatics/btu703
Quinn M, Angelico MC, Warram JH, Krolewski AS (1996) Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 39:940–945
Sandholm N, Salem RM, McKnight AJ et al (2012) New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet. doi:10.1371/journal.pgen.1002921
Sawcer S, Hellenthal G, Pirinen M et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219. doi:10.1038/nature10251
Seaquist ER, Goetz FC, Rich S, Barbosa J (1989) Familial clustering of diabetic kidney disease. N Engl J Med 320:1161–1165. doi:10.1056/NEJM198905043201801
Shih NY, Li J, Karpitskii V et al (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286:312–315
Shukrun R, Vivante A, Pleniceanu O et al (2014) A human integrin-α3 mutation confers major renal developmental defects. PLoS One 9:e90879. doi:10.1371/journal.pone.0090879
Skorecki K, Wasser WG (2016) Beyond APOL1: genetic inroads into understanding population disparities in diabetic kidney disease. Clin J Am Soc Nephrol 11:928–931. doi:10.2215/CJN.04680416
Škrtić M, Cherney DZI (2015) Sodium–glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens 24:96–103. doi:10.1097/MNH.0000000000000084
Spray BJ, Atassi NG, Tuttle AB, Freedman BI (1995) Familial risk, age at onset, and cause of end-stage renal disease in white Americans. J Am Soc Nephrol JASN 5:1806–1810
Tzur S, Rosset S, Shemer R et al (2010) Missense mutations in the APOL1. Hum Genet 128:345–350. doi:10.1007/s00439-010-0861-0
United States Renal Data System (2014) 2014 USRDS annual data report: epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda
Voskarides K, Damianou L, Neocleous V et al (2007) COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy. J Am Soc Nephrol 18:3004–3016. doi:10.1681/ASN.2007040444
Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164–e164. doi:10.1093/nar/gkq603
Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191. doi:10.1093/bioinformatics/btq340
Wu MC, Lee S, Cai T et al (2011) Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 89:82–93. doi:10.1016/j.ajhg.2011.05.029
Yates A, Akanni W, Amode MR et al (2016) Ensembl 2016. Nucleic Acids Res 44:D710–D716. doi:10.1093/nar/gkv1157
Yeo NC, O’Meara CC, Bonomo JA et al (2015) Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity. Genome Res 25:57–65. doi:10.1101/gr.182881.114
Yu ASL (2015) Claudins and the kidney. J Am Soc Nephrol JASN 26:11–19. doi:10.1681/ASN.2014030284
Zhou W, Dai J, Attanasio M, Hildebrandt F (2010) Nephrocystin-3 is required for ciliary function in zebrafish embryos. Am J Physiol Ren Physiol 299:F55–F62. doi:10.1152/ajprenal.00043.2010
Acknowledgments
This work was supported by NIH Grants R01 DK53591 (DWB), DK070941, and DK084149 (BIF), and by the National Natural Science Foundation of China (No. 81200488). This work has also been made possible through an International Society of Nephrology Fellowship and Shanghai Jiaotong University K.C. Wong Medical Fellowship Fund (Jun Ma). We acknowledge the contributions of the study participants, coordinators, physicians, staff, and laboratory.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
M. Guan and J. Ma were equal contributors.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Guan, M., Ma, J., Keaton, J.M. et al. Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans. Hum Genet 135, 1251–1262 (2016). https://doi.org/10.1007/s00439-016-1714-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-016-1714-2