Genome-Wide Scans for Diabetic Nephropathy and Albuminuria in Multiethnic Populations

Iyengar, Sudha K.; Abboud, Hanna E.; Goddard, Katrina A.B.; Saad, Mohammed F.; Adler, Sharon G.; Arar, Nedal H.; Bowden, Donald W.; Duggirala, Ravi; Elston, Robert C.; Hanson, Robert L.; Ipp, Eli; Kao, W. H. Linda; Kimmel, Paul L.; Klag, Michael J.; Knowler, William C.; Meoni, Lucy A.; Nelson, Robert G.; Nicholas, Susanne B.; Pahl, Madeleine V.; Parekh, Rulan S.; Quade, Shannon R E; Rich, Stephen S.; Rotter, Jerome I.; Scavini, Marina; Schelling, Jeffrey R.; Sedor, John R.; Sehgal, Ashwini R.; Shah, Vallabh O.; Smith, Michael W.; Taylor, Kent D.; Winkler, Cheryl A.; Zager, Philip G.; Freedman, Barry I.

doi:10.2337/db06-1154

Cited by 143 publications

(112 citation statements)

References 31 publications

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“…EPO is located on 7q21, and our results are consistent with previous reports that chromosome 7q21 harbors a locus for increased susceptibility to diabetic nephropathy (11)(12)(13)(14). The risk allele (T) is associated with elevated EPO in the vitreous body of the human eye and mouse models of diabetic eye and kidney complications.…”

Section: Discussionsupporting

confidence: 91%

“…A growing number of genome-wide linkage scans have been performed to detect diabetic nephropathy susceptibility loci. Case-control studies have examined possible roles for various candidate gene singlenucleotide polymorphisms (SNPs), and linkage analysis has suggested a diabetic nephropathy locus on chromosome 3q (9)(10)(11). Other loci have also been suggested (reviewed in ref.…”

mentioning

confidence: 99%

“…11). Recently, several reports implicate a locus at chromosome 7q21 as a modifier of the risk of nephropathy in diabetes (11)(12)(13)(14), but a specific gene has not been identified.…”

mentioning

confidence: 99%

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Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Tong

Yang

Patel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

188

191

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Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P ‫؍‬ 1.91 ؋ 10 ؊3 ; Genetics of Kidneys in Diabetes (GoKinD) Study: P ‫؍‬ 2.66 ؋ 10 ؊8 ; and Boston: P ‫؍‬ 2.1 ؋ 10 ؊2 ]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. diabetic microvascular complication ͉ end stage renal disease ͉ proliferative diabetic retinopathy ͉ SNP ͉ association

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

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Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Tong

Yang

Patel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

188

191

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“…Six complete genome-wide linkage scans have been published in type 2 DN, with one in type 1 DN (and another partial genome scan in type 1 DN) (14,(23)(24)(25)(26)(27)(28)(29). Although most of these analyses evaluated small numbers of families from different ethnic groups, several consistent regions of linkage have been detected (Table 1).…”

Section: Genome-wide Linkage Scans For Dnmentioning

confidence: 99%

“…Several regions of linkage have been replicated among the various groups with type 2 DN, as well. The 18q22-23 linkage region was replicated in four populations (23,26,29), the 7q35-36 peak in three reports (25,26,31), and the 7p15 and 10q26 peaks in two each (14,23,32). Positional candidate genes for DN in these regions are now being sought and identified (Table 2).…”

Section: Genome-wide Linkage Scans For Dnmentioning

confidence: 99%

Genetic Factors in Diabetic Nephropathy

Freedman

Bostrom

Daeihagh

et al. 2007

Clinical Journal of the American Society of Nephrology

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173

125

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Several genes that predispose to type 2 diabetes have recently been identified. In addition to the recognized and powerful effects of environmental factors, there is abundant evidence in support of genetic susceptibility to the microvascular complication of nephropathy in individuals with both type 1 and type 2 diabetes. Familial aggregation of phenotypes such as end-stage renal disease, albuminuria, and chronic kidney disease have routinely been reported in populations throughout the world, and heritability estimates for albuminuria and glomerular filtration rate demonstrate strong contributions of inherited factors. Recent genome-wide linkage scans have identified several chromosomal regions that likely contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under these linkage peaks. These complimentary approaches have demonstrated that polymorphisms in the carnosinase 1 gene on chromosome 18q, the adiponectin gene on 3q, and the engulfment and cell motility gene on 7p are likely associated with susceptibility to diabetic nephropathy. Additional genes that seem to be of importance in renal phenotypes include manganese superoxide dismutase and angiotensin 1-converting enzyme, with nitric oxide synthase implicated in albuminuria. This article reviews the inherited aspects of diabetic kidney disease with particular emphasis on recently implicated genes and pathways. It seems likely that the risk for diabetes-associated kidney disease is magnified by inheriting risk alleles at several susceptibility loci, in the presence of hyperglycemia.Clin J Am Soc Nephrol 2: 1306 -1316, 2007. doi: 10.2215/CJN.02560607 I t was previously thought that individuals who had diabetes and developed progressive diabetic nephropathy (DN) and/or ESRD were simply exposed to long durations of diabetes with relatively poor glycemic control. In other words, all individuals with diabetes were assumed to be at essentially equivalent risk for developing nephropathy, allowing for differences in their ambient serum glucose concentration. In support of the concept that exposure to a hyperglycemic environment led to DN (often with coexisting obesity, metabolic syndrome, hypertension, and hyperlipidemia), clinical trials have conclusively demonstrated that improving glycemic control delays and, in some cases, may prevent the subsequent development of albuminuria, DN, and macrovascular complications such as coronary artery disease (1,2). The concept that select individuals with diabetes were at differential risk for developing nephropathy on the basis of familial aggregation of kidney disease was initially reported in 1989 but has only recently gained broad acceptance among nephrologists and diabetologists (3). Familial Aggregation of DNThe notion that genetic factors contribute to any complex disease rests on the demonstration of familial aggregation. Familial clustering of nephropathy could result from shared genes, environmental exposures, or their combination.After repeated demonstra...

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