Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes.

Sex and genetic variation influence the risk of developing diabetic nephropathy and ESRD in patients with type 1 diabetes. We performed a genome-wide association study in a cohort of 3652 patients from the Finnish Diabetic Nephropathy (FinnDiane) Study with type 1 diabetes to determine whether sex-specific genetic risk factors for ESRD exist. A common variant, rs4972593 on chromosome 2q31.1, was associated with ESRD in women (P<5×10(-8)) but not in men (P=0.77). This association was replicated in the meta-analysis of three independent type 1 diabetes cohorts (P=0.02) and remained significant for women (P<5×10(-8); odds ratio, 1.81 [95% confidence interval, 1.47 to 2.24]) upon combined meta-analysis of the discovery and replication cohorts. rs4972593 is located between the genes that code for the Sp3 transcription factor, which interacts directly with estrogen receptor α and regulates the expression of genes linked to glomerular function and the pathogenesis of nephropathy, and the CDCA7 transcription factor, which regulates cell proliferation. Further examination revealed potential transcription factor-binding sites within rs4972593 and predicted eight estrogen-responsive elements within 5 kb of this locus. Moreover, we found sex-specific differences in the glomerular expression levels of SP3 (P=0.004). Overall, these results suggest that rs4972593 is a sex-specific genetic variant associated with ESRD in patients with type 1 diabetes and may underlie the sex-specific protection against ESRD.

[1]  悠輔 佐田.  豪州メルボルン Baker IDI Heart and Diabetes Institute , 2015 .

[2]  A. Krolewski,et al.  Diabetic nephropathy: is ESRD its only heritable phenotype? , 2013, Journal of the American Society of Nephrology : JASN.

[3]  Benjamin J. Keller,et al.  New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes , 2012, PLoS genetics.

[4]  Eurie L. Hong,et al.  Annotation of functional variation in personal genomes using RegulomeDB , 2012, Genome research.

[5]  Melissa J. Morine,et al.  Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy. , 2012, Biochimica et biophysica acta.

[6]  P. Deloukas,et al.  Patterns of Cis Regulatory Variation in Diverse Human Populations , 2012, PLoS genetics.

[7]  F. Maquart,et al.  The p65 Subunit of NF-κB Inhibits COL1A1 Gene Transcription in Human Dermal and Scleroderma Fibroblasts through Its Recruitment on Promoter by Protein Interaction with Transcriptional Activators (c-Krox, Sp1, and Sp3)* , 2011, The Journal of Biological Chemistry.

[8]  K. Suszták,et al.  Transcriptome Analysis of Human Diabetic Kidney Disease , 2011, Diabetes.

[9]  C. Forsblom,et al.  Sex-related differences in the long-term risk of microvascular complications by age at onset of type 1 diabetes , 2011, Diabetologia.

[10]  S. Doublier,et al.  Estrogens and progression of diabetic kidney damage. , 2011, Current diabetes reviews.

[11]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[12]  Serafino Pantano,et al.  Differential Control of Notch1 Gene Transcription by Klf4 and Sp3 Transcription Factors in Normal versus Cancer-Derived Keratinocytes , 2010, PloS one.

[13]  Jennifer K. Sun,et al.  Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications , 2008, Proceedings of the National Academy of Sciences.

[14]  C. Maric,et al.  Estrogens and the diabetic kidney. , 2008, Gender medicine.

[15]  S. Silbiger,et al.  Gender and human chronic renal disease. , 2008, Gender medicine.

[16]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[17]  R. Lattanzio,et al.  The Therapeutic Potential of VEGF Inhibition in Diabetic Microvascular Complications , 2007, American journal of cardiovascular drugs : drugs, devices, and other interventions.

[18]  Felix Eichinger,et al.  Modular Activation of Nuclear Factor-κB Transcriptional Programs in Human Diabetic Nephropathy , 2006, Diabetes.

[19]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[20]  Merlin C. Thomas,et al.  Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). , 2005, Diabetes care.

[21]  C. Dang,et al.  The Myc target gene JPO1/CDCA7 is frequently overexpressed in human tumors and has limited transforming activity in vivo. , 2005, Cancer research.

[22]  R. Elston,et al.  The Family Investigation of Nephropathy and Diabetes (FIND): design and methods. , 2005, Journal of diabetes and its complications.

[23]  Adeyemo,et al.  Faculty of Health Sciences , 2005 .

[24]  J. Tuomilehto,et al.  Population-based assessment of familial clustering of diabetic nephropathy in type 1 diabetes. , 2004, Diabetes.

[25]  Brad Saville,et al.  Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor α and SP proteins , 2004, Oncogene.

[26]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[27]  R. Cotran,et al.  CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. , 2001, The American journal of pathology.

[28]  M. Saleem,et al.  Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. , 2001, The Journal of clinical investigation.

[29]  S. Safe,et al.  Inhibition of Vascular Endothelial Growth Factor Expression in HEC1A Endometrial Cancer Cells through Interactions of Estrogen Receptor α and Sp3 Proteins* , 2000, The Journal of Biological Chemistry.

[30]  J. Zhang,et al.  What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. , 1998, JAMA.

[31]  L. Kuller,et al.  Predictors of Microalbuminuria in Individuals with IDDM: Pittsburgh Epidemiology of Diabetes Complications Study , 1993, Diabetes Care.