Genetics of Kidneys in Diabetes (GoKinD) Study

Mueller, Patricia W.; Rogus, John; Cleary, Patricia A.; Zhao, Yuan; Smiles, Adam M.; Steffes, Michael W.; Bucksa, Jean M.; Gibson, Therese B.; Cordovado, Suzanne K.; Królewski, Andrzej S.; Nierras, Concepcion R.; Warram, James H.

doi:10.1681/asn.2005080822

Cited by 119 publications

(141 citation statements)

References 21 publications

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“…We chose only European-American individuals in the GoKinD collection and excluded patients or controls with other ethnicities. In total, there were 865 cases in the GoKinD cohort, including 365 T1D patients with both ESRD and PDR, 500 with nephropathy (proteinuria with urine albumin to creatinine ratio Ͼ300) and retinopathy without progression to PDR and ESRD, and 574 T1D diabetic control patients without retinopathy and nephropathy (16 Table S4). The association extended to T1D individuals with significant nephropathy and retinopathy but who have not progressed to ESRD (500 cases, P ϭ 6.25 ϫ 10 Ϫ6 , Table S4).…”

Section: Resultsmentioning

confidence: 99%

“…Panretinal laser treatment is used as an indication of PDR. Details of the GoKinD study are available online (www.jdrf.org/gokind) and are published (16). Boston patients were diagnosed and enrolled at the Joslin Diabetic Center, and Utah patients were diagnosed and enrolled at the Moran Eye Center and renal dialysis facilities of the University of Utah.…”

Section: Methodsmentioning

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: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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“…Self-reported sex was confirmed using the AmpFlSTR Green I PCR Amplifi-cation Kit (Applied Biosystems, Foster City, CA) with modifications. Detailed extraction and quality control methods can be found in the supplementary material of Mueller et al (6). Genotyping methods.…”

Section: Methodsmentioning

confidence: 99%

“…The Genetics of Kidneys in Diabetes (GoKinD) study, an initiative supported by the Juvenile Diabetes Research Foundation, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Centers for Disease Control and Prevention (CDC), was created to address this research gap (6). The GoKinD study includes 1,879 individuals with long-term type 1 diabetes, approximately half with nephropathy (defined as persistent proteinuria or ESRD) and half without, and extensive phenotypic data.…”

mentioning

confidence: 99%

Nephropathy in Type 1 Diabetes Is Diminished in Carriers of HLA-DRB1*04

et al. 2008

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OBJECTIVE—The purpose of this study was to examine whether known genetic risk factors for type 1 diabetes (HLA-DRB1, -DQA1, and -DQB1 and insulin locus) play a role in the etiology of diabetic nephropathy. RESEARCH DESIGN AND METHODS—Genetic analysis of HLA-DRB1, -DQA1, -DQB1 and the insulin gene (INS) was performed in the Genetics of Kidneys in Diabetes (GoKinD) collection of DNA (European ancestry subset), which includes case patients with type 1 diabetes and nephropathy (n = 829) and control patients with type 1 diabetes but not nephropathy (n = 904). The availability of phenotypic and genotypic data on GoKinD participants allowed a detailed analysis of the association of these genes with diabetic nephropathy. RESULTS—Diabetic probands who were homozygous for HLA-DRB1*04 were 50% less likely to have nephropathy than probands without any DRB1*04 alleles. In heterozygous carriers, a protective effect of this allele was not as clearly evident; the mode of inheritance therefore remains unclear. This association was seen in probands with both short (<28 years, P = 0.02) and long (≥28 years, P = 0.0001) duration of diabetes. A1C, a marker of sustained hyperglycemia, was increased in control probands with normoalbuminuira, despite long-duration diabetes, from 7.2 to 7.3 to 7.7% with 0, 1, and 2 copies of the DRB1*04 allele, respectively. This result is consistent with a protective effect of DRB1*04 that may allow individuals to tolerate higher levels of hyperglycemia, as measured by A1C, without developing nephropathy. CONCLUSIONS—These data suggest that carriers of DRB1*04 are protected from some of the injurious hyperglycemic effects related to nephropathy. Interestingly, DRB1*04 appears to be both a risk allele for type 1 diabetes and a protective allele for nephropathy.

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“…Multiple factors, including an interaction between hyperglycemia-induced metabolic and hemodynamic changes [1] and genetic predisposition [2], have been shown to contribute to the development of DN. Currently, the mainstay of therapy for DN is improving glucose control and lowering systemic blood pressure with reninangiotensin system inhibitors.…”

mentioning

confidence: 99%