Genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, and research efforts have been invested worldwide to identify the susceptibility gene for diabetic nephropathy. Although, several candidate genes were shown to be associated with the disease, the results were not always consistent; most of the genes conferring susceptibility to diabetic nephropathy remain to be identified. Recent development of the single nucleotide polymorphism (SNP) typing technology and collation of information on linkage disequilibrium in the human genome have facilitated genome-wide association studies (GWASs) for investigating novel disease-susceptibility genes across the entire human genome. GWASs are considered a powerful and promising approach and are expected to be useful for identifying convincing susceptibility genes for several common diseases; however, to date, these studies have not been able to completely cover the entire human genome.
Al-Kateb, H., Boright, A.P., Mirea, L., Xie, X., Sutradhar, R., Mowjoodi, A. et al. (2008) Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy: the diabetes control and complications trial/epidemiology of diabetes interventions and complications genetics study . Diabetes57: 218-228.
2.
Araki, S., Moczulski, D.K., Hanna, L., Scott, L.J., Warram, J.H. and Krolewski, A.S. (2000) APOE polymorphisms and the development of diabetic nephropathy in type 1 diabetes: results of case-control and family-based studies . Diabetes49: 2190-2195.
3.
Araki, S., Ng, D.P., Krolewski, B., Wyrwicz, L., Rogus, J.J., Canani, L. et al. (2003) Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus . J Am Soc Nephrol14: 2015-2024.
4.
Araki, S., Haneda, M., Sugimoto, T., Isono, M., Isshiki, K., Kashiwagi, A. et al. (2005) Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes. Diabetes54: 2983-2987.
5.
Bowden, D.W., Colicigno, C.J., Langefeld, C.D., Sale, M.M., Williams, A., Anderson, P.J. et al. (2004) A genome scan for diabetic nephropathy in African Americans. Kidney Int66: 1517-1526.
6.
Brownlee, M. (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes54: 1615-1625.
7.
Brugnera, E., Haney, L., Grimsley, C., Lu, M., Walk, S.F., Tosello-Trampont, A.C. et al. (2002) Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nature Cell Biol4: 574-582.
8.
Canani, L.H., Ng, D.P., Smiles, A., Rogus, J.J., Warram, J.H. and Krolewski, A.S. (2002) Polymorphism in ecto-nucleotide pyrophosphatase/ phosphodiesterase 1 gene (ENPP1/PC-1) and early development of advanced diabetic nephropathy in type 1 diabetes. Diabetes51: 1188-1193.
9.
Fava, S., Azzopardi, J., Hattersley, A.T. and Watkins, P.J. (2000) Increased prevalence of proteinuria in diabetic sibs of proteinuric type 2 diabetic subjects. Am J Kidney Dis35: 708-712.
10.
Foley, R.N. and Colins, A.J. (2007) End-stage renal disease in the United States: an update from the United States Renal Data System. J Am Soc Nephrol18: 2644-2648.
11.
Freire, M.B., Ji, L., Onuma, T., Orban, T., Warram, J.H. and Krolewski, A.S. (1998) Gender-specific association of M235T polymorphism in angiotensinogen gene and diabetic nephropathy in NIDDM. Hypertension31: 896-899.
12.
Fujisawa, T., Ikegami, H., Kawaguchi, Y., Hamada, Y., Ueda, H., Shintani, M. et al. (1998) Meta-analysis of association of insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy. Diabetologia41: 47-53.
13.
Gaede, P., Vedel, P., Larsen, N., Jensen, G.V., Parving, H.H. and Pedersen, O. (2003) Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med348: 383-393.
14.
Gaede, P., Tarnow, L., Vedel, P., Parving, H.H. and Pedersen, O. (2004) Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria . Nephrol Dial Transplant19: 2784-2788.
15.
Goodkin, D.A., Bragg-Gresham, J.L., Koenig, K.G., Wolfe, R.A., Akiba, T., Andreucci, V.E. et al. (2003) Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS). J Am Soc Nephrol14: 3270-3277.
16.
Gumienny, T.L., Brugnera, E., Tosello-Trampont, A.C., Kinchen, J.M., Haney, L.B. et al. (2001) CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell107: 27-41.
17.
Haga, H., Yamada, R., Ohnishi, Y., Nakamura, Y. and Tanaka, T. (2002) Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190,562 genetic variation in the human genome. J Hum Genet47: 605-610.
18.
Hanson, R.L., Craig, D.W., Millis, M.P., Yeatts, K.A., Kobes, S., Pearson, J.V. et al. (2007) Identification of PVT1 as a candidate gene for end-stage renal disease in type 2 diabetes using a pooling-based genome-wide single nucleotide polymorphism association study. Diabetes56: 975-983.
19.
Hirakawa, M., Tanaka, T., Hashimoto, Y., Kuroda, M., Takagi, T. and Nakamura, Y. (2002) JSNP: a database of common gene variations in the Japanese population. Nucleic Acids Res30: 158-162.
20.
Imperatore, G., Hanson, R.L., Pettitt, D.J., Kobes, S., Bennett, P.H. and Knowler, W.C. (1998) Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes47: 821-830.
21.
International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature431: 931-945.
22.
Jacobsen, P., Tarnow, L., Carstensen, B., Hovind, P., Poirier, O. and Parving, H.H. (2003) Genetic variation in the renin-angiotensin system and progression of diabetic nephropathy. J Am Soc Nephrol14: 2843-2850.
23.
Janssen, B., Hohenadel, D., Brinkkoetter, P., Peters, V., Rind, N., Fischer, C. et al. (2005) Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1 . Diabetes54: 2320-2327.
24.
Jorsal, A., Tarnow, L., Lajer, M., Ek, J., Hansen, T., Pedersen, O., et al., (2008) The PPARgamma2 Pro12Ala variant predicts ESRD and mortality in patients with type 1 diabetes and diabetic nephropathy . Mol Genet Metab May 6 [Epub ahead of print].
25.
Kamiyama, M., Kobayashi, M., Araki, S., Iida, A., Tsunoda, T., Kawai, K. et al. (2007) Polymorphisms in the 3' UTR in the neurocalcin δ gene affect mRNA stability, and confer susceptibility to diabetic nephropathy . Human Genet122: 397-407.
26.
Keene, K.L., Mychaleckyj, J.C., Smith, S.G., Leak, T.S., Perlegas, P.S., Langefeld, C.D. et al. (2008) Comprehensive evaluation of the estrogen receptor alpha gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population. Hum Genet123: 333-341.
27.
Kim, J.H., Shin, H.D., Park, B.L., Moon, M.K., Cho, Y.M., Hwang, Y.H. et al. (2006) SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. Diabetes55: 843-848.
28.
Krolewski, A.S., Warram, J.H., Rand, L.I. and Kahn, C.R. (1987) Epidemiologic approach to the etiology of type 1 diabetes mellitus and its complications. N Engl J Med317: 1390-1398.
29.
Krolewski, A.S., Poznik, G.D., Placha, G., Canani, L., Dunn, J., Walker, W. et al. (2006) A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes. Kidney Int69: 129-136.
30.
Lin, H.Y., Wang, C.L., Hsiao, P.J., Lu, Y.C., Chen, S.Y., Lin, K.D. et al. (2007) SUMO4 M55V variant is associated with diabetic nephropathy in type 2 diabetes. Diabetes56: 1177-1180.
31.
Liu, Y. (2004) Epithelial mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention . J Am Soc Nephrol15: 1-12.
32.
Lyengar, S.K., Abboud, H.E., Goddard, K.A., Saad, M.F., Adler, S.G., Arar, N.H. et al. (2007) Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes56: 1577-1585.
33.
Maeda, S., Haneda, M., Yasuda, H., Tachikawa, T., Isshiki, K., Koya, D. et al. (1999) Diabetic nephropathy is not associated with the dinucleotide repeat polymorphism upstream of the aldose reductase (ALR2) gene but with erythrocyte aldose reductase content in Japanese subjects with type 2 diabetes. Diabetes48: 420-422.
34.
Maeda, S., Haneda, M., Guo, B., Koya, D., Hayashi, K., Sugimoto, T. et al. (2001) Dinucleotide repeat polymorphism of matrix metalloproteinase-9 gene is associated with nephropathy in Japanese subjects with type 2 diabetes. Kidney Int60: 1428-1434.
35.
Maeda, S. (2004) Genome-wide search for susceptibility gene to diabetic nephropathy by gene-based SNP. Diabetes Res Clin Pract66(Suppl 1): S45-S47.
36.
Maeda, S., Osawa, N., Hayashi, T., Tsukada, S., Kobayashi, M. and Kikkawa, R. (2007) Genetic variations associated with diabetic nephropathy and type 2 diabetes in a Japanese population. Kidney Int72: S43-S48.
37.
Marre, M., Jeunemaitre, X., Gallois, Y., Rodier, M., Chatellier, G., Sert, C. et al. (1997) Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes. J Clin Invest99: 1585-1595.
38.
McKnight, A.J., Maxwell, A.P., Sawcer, S., Compston, A., Setakis, E., Patterson, C.C. et al. (2006) A genome-wide DNA microsatellite association screen to identify chromosomal regions harboring candidate genes in diabetic nephropathy. J Am Soc Nephrol17: 831-836.
39.
Mizuiri, S., Hemmi, H., Kumanomidou, H., Iwamoto, M., Miyagi, M., Sakai, K. et al. (2001) Angiotensin-converting enzyme (ACE) I/D genotype and renal ACE gene expression. Kidney Int60: 1124-1130.
40.
Moczulski, D.K., Rogus, J.J., Antonellis, A., Warram, J.H. and Krolewski, A.S. (1998) Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis . Diabetes47: 1164-1169.
41.
Nakai, S., Shinzato, T., Nagura, Y., Masakane, I., Kitaoka, T., Shinoda, T. et al. (2004) An overview of regular dialysis treatment in Japan (as of 31 December 2001)Ther Apher Dial8: 3-32.
42.
Nakajima, K., Tanaka, Y., Nomiyama, T., Ogihara, T., Piao, L., Sakai, K. et al. (2002) Chemokine receptor genotype is associated with diabetic nephropathy in Japanese with type 2 diabetes. Diabetes51: 238-242.
43.
Navarro-González, J.F. and Mora-Fernández, C. (2008) The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol19: 433-442.
44.
Ng, D.P., Warram, J.H. and Krolewski, A.S. (2003) TGF-beta 1 as a genetic susceptibility locus for advanced diabetic nephropathy in type 1 diabetes mellitus: an investigation of multiple known DNA sequence variants. Am J Kidney Dis41: 22-28.
45.
Ng, D.P., Tai, B.C., Koh, D., Tan, K.W. and Chia, K.S. (2005) Angiotensin-I converting enzyme insertion/deletion polymorphism and its association with diabetic nephropathy: a meta-analysis of studies reported between 1994 and 2004 and comprising 14,727 subjects. Diabetologia48: 1008-1016.
46.
Ng, D.P., Placha, G., Choo, S., Chia, K.S., Warram, J.H. and Krolewski, A.S. (2006) A disease haplotype for advanced nephropathy in type 2 diabetes at the ACE locus. Diabetes55: 2660-2663.
47.
Ng, D.P., Nurbaya, S., Choo, S., Koh, D., Chia, K.S. and Krolewski, A.S. (2008) Genetic variation at the SLC12A3 locus is unlikely to explain risk for advanced diabetic nephropathy in Caucasians with type 2 diabetes. Nephrol Dial Transplant23(7): 2260-4. [Epub Feb 10 2008].
48.
Nishiyama, K., Tanaka, Y., Nakajima, K., Mokubo, A., Atsumi, Y., Matsuoka, K. et al. (2005) Polymorphism of the solute carrier family 12 (sodium/ chloride transporters) member 3, SLC12A3, gene at exon 23 (+78G/A: Arg913Gln) is associated with elevation of urinary albumin excretion in Japanese patients with type 2 diabetes: a 10-year longitudinal study. Diabetologia48: 1335-1338.
49.
Nomiyama, T., Tanaka, Y., Piao, L., Nagasaka, K., Sakai, K., Ogihara, T. et al. (2003) The polymorphism of manganese superoxide dismutase is associated with diabetic nephropathy in Japanese type 2 diabetic patients. J Hum Genet48: 138-141.
50.
Ohkubo, Y., Kishikawa, H., Araki, E., Miyata, T., Isami, S., Motoyoshi, S. et al. (1995) Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract28: 103-117.
51.
Ohnishi, Y., Tanaka, T., Ozaki, K., Yamada, R., Suzuki, H. and Nakamura, Y. (2001) A high-throughput SNP typing system for genome-wide association studies. J Hum Genet46: 471-477.
52.
Osawa, N., Koya, D., Araki, S., Uzu, T., Tsunoda, T., Kashiwagi, A. et al. (2007) Combinational effect of genes for the renin-angiotensin system in conferring susceptibility to diabetic nephropathy. J Hum Genet52: 143-151.
53.
Osterholm, A.M., He, B., Pitkaniemi, J., Albinsson, L., Berg, T., Sarti, C. et al. (2007) Genome-wide scan for type 1 diabetic nephropathy in the Finnish population reveals suggestive linkage to a single locus on chromosome 3q. Kidney Int71: 140-145.
54.
Perkins, B.A., Ficociello, L.H., Silva, K.H., Finkelstein, D.M., Warram, J.H. and Krolewski, A.S. (2003) Regression of microalbuminuria in type 1 diabetes . N Engl J Med348: 2285-2293.
55.
Placha, G., Poznik, G.D., Dunn, J., Smiles, A., Krolewski, B., Glew, T. et al. (2006) A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes. Diabetes55: 3358-3365.
56.
Quinn, M., Angelico, M.C., Warram, J.H. and Krolewski, A.S. (1996) Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia39: 940-945.
57.
Rayner, H.C., Pisoni, R.L., Bommer, J., Canaud, B., Hecking, E., Locatelli, F. et al. (2004) Mortality and hospitalization in haemodialysis patients in five European countries: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant19: 108-120.
58.
Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P. and Soubrier, F. (1990) An insertion/ deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest86: 1343-1346.
59.
Saxena, R., Voight, B.F., Lyssenko, V., Burtt, N.P., de Bakker, P.I. and Chen, H. (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science316: 1331-1336.
60.
Schelling, J.R., Abboud, H.E., Nicholas, S.B., Pahl, M.V., Sedor, J.R., Adler, S.G. et al. (2008) Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes57: 235-243.
61.
Scott, L.J., Mohlke, K.L., Bonnycastle, L.L., Willer, C.J., Li, Y., Duren, W.L. et al. (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple suceptibility variants. Science316: 1341-1345.
62.
Shimazaki, A., Kawamura, Y., Kanazawa, A., Sekine, A., Saito, S., Tsunoda, T. et al. (2005) Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes54: 1171-1178.
63.
Shimazaki, A., Tanaka, Y., Shinosaki, T., Ikeda, M., Watada, H., Hirose, H. et al. (2006) ELMO1 increases expression of extracellular matrix (ECM) proteins and inhibits cell adhesion to ECMs. Kidney Int70: 1769-1776.
64.
Simon, D.B., Nelson-Williams, C., Johnson-Bia, M., Ellison, D., Karet, F.E., Morey-Molina, A. et al. (1996) Gitelman's variant of Bartters syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nait Genet12: 24-30.
65.
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D. et al. (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature445: 881-885.
66.
Steinthorsdottir, V., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Jonsdottir, T., Walters, G.B. et al. (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet39: 770-775.
67.
Tanaka, N., Babazono, T., Saito, S., Sekine, A., Tsunoda, T., Haneda, M. et al. (2003) The association of solute carrier family 12 (sodium/chloride) member 3 with diabetic nephropathy, identified by genome-wide analyses of SNPs. Diabetes52: 2848-2853.
68.
The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med329: 977-986.
69.
The International HapMap Consortium (2005) A haplotype map of the human genome. Nature437: 1299-1320.
70.
Tomino, Y., Makita, Y., Shike, T., Gohda, T., Haneda, M., Kikkawa, R. et al. (1999) Relationship between polymorphism in the angiotensinogen, angiotensin-converting enzyme or angiotensin II receptor and renal progression in Japanese NIDDM patients. Nephron82: 139-144.
71.
UK Prospective Diabetes Study (UKPDS) Group ( 1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS33). Lancet352: 837-853.
72.
Vardarli, I., Baier, L.J., Hanson, R.L., Akkoyun, I., Fischer, C., Rohmeiss, P. et al. (2002) Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23. Kidney Int62: 2176-2183.
73.
Vionnet, N., Tregouët, D., Kazeem, G., Gut, I., Groop, P.H., Tarnow, L. et al. (2006) Analysis of 14 candidate genes for diabetic nephropathy on chromosome 3q in European populations: strongest evidence for association with a variant in the promoter region of the adiponectin gene . Diabetes55: 3166-3174.
74.
Xu, M., Chen, X., Yan, L., Cheng, H. and Chen, W. (2008) Association between (AC)n dinucleotide repeat polymorphism at the 5'-end of the aldose reductase gene and diabetic nephropathy: a meta-analysis . J Mol Endocrinol40: 243-251.
75.
Zanchi, A., Moczulski, D.K., Hanna, L.S., Wantman, M., Warram, J.H. et al. (2000) Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int57: 405-413.
76.
Zeggini, E., Weedon, M.N., Lindgren, C.M., Frayling, T.M., Elliott, K.S., Lango, H. et al. (2007) Replication of genome-wide association signal in U.K. samples reveals risk loci for type 2 diabetes. Science316: 1336-1341.
77.
Zeggini, E., Scott, L.J., Saxena, R., Voight, B.F., Marchini, J.L., Hu, T. et al. (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet25(2) 35-40. March 30; [Epub ahead of print].
78.
Zintzaras, E. and Stefanidis, I. (2005) Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis. J Hum Genet50: 84-91.
79.
Zintzaras, E., Uhlig, K., Koukoulis, G.N., Papathanasiou, A.A. and Stefanidis, I. (2007) Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis. J Hum Genet52: 881-890.
80.
Zychma, M.J., Zukowska-Szczechowska, E., Lacka, B.I. and Grzeszczak, W. (2000) Angiotensinogen M235T and chymase gene CMA/B polymorphisms are not associated with nephropathy in type II diabetes. Nephrol Dial Transplant15: 1965-1970.
