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      New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 1 , 2 , 10 , 7 , 6 , 11 , 8 , 9 , 1 , 2 , 12 , 7 , 4 , 5 , 13 , 14 , 15 , 16 , 17 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 18 , 19 , 1 , 2 , 1 , 20 , 1 , 20 , 21 , 1 , 2 , 1 , 2 , 19 , 1 , 2 , 22 , 1 , 2 , 1 , 2 , 22 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 23 , 1 , 2 , 19 , 18 , 24 , 25 , 26 , 1 , 2 , 27 , 28 , 4 , 4 , 4 , 11 , 29 , 30 , DCCT/EDIC Research Group 31 , 32 , 33 , 34 , 34 , 35 , 34 , 35 , 14 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 43 , 44 , 45 , 44 , 46 , 47 , 48 , 48 , 48 , 49 , 47 , 50 , 50 , 51 , 15 , 49 , 44 , 44 , 45 , 43 , 52 , 53 , 39 , 40 , 54 , 14 , 35 , 55 , 56 , 55 , 30 , 56 , 7 , 28 , 8 , 9 , 4 , 5 , 6 , * , 8 , 9 , * , 4 , 6 , 11 , * , 1 , 2 , 57 , * , 7 , 58 , *

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          Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene ( P = 1.2×10 −8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 ( P = 2.0×10 −9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10 −7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

          Author Summary

          The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.

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          Most cited references 37

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          Newly identified loci that influence lipid concentrations and risk of coronary artery disease.

          To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.
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            Multiple loci associated with indices of renal function and chronic kidney disease.

            Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.
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              Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus.

              Kidney disease in type 2 diabetes mellitus (DM) is more heterogeneous than in type 1 DM. Reduced glomerular filtration rate (GFR) among individuals with type 2 DM may not always be due to classic diabetic glomerulosclerosis, which is associated with albuminuria and retinopathy. To determine the prevalence of chronic renal insufficiency (CRI), defined as a GFR less than 60 mL/min per 1.73 m2 body surface area (BSA) in the absence of microalbuminuria or macroalbuminuria and diabetic retinopathy among adults with type 2 DM. Cross-sectional analysis of adults aged 40 years or older with type 2 DM in the Third National Health and Nutrition Examination Survey, a probability sample of the total civilian US noninstitutionalized population conducted from 1988-1994. The GFR per 1.73 m2 BSA, calculated with serum creatinine, urea nitrogen, and serum albumin levels using the Modification of Diet in Renal Disease Study prediction equation; albuminuria, assessed using spot urine albumin/creatinine ratio; and presence of retinopathy, determined with fundus photography. Overall, 13% (sampled n = 171) of adults with type 2 DM (n = 1197) had CRI with a population estimate of 1.1 million. Among these adults with CRI, diabetic retinopathy was noted in 28% (n = 58), while the frequencies of microalbuminuria and macroalbuminuria were 45% (n = 64) and 19% (n = 47), respectively. Retinopathy and albuminuria (microalbuminuria or macroalbuminuria) were both absent in 30% (n = 51) of adults with type 2 DM and CRI. The population estimate of adults with type 2 DM and CRI in the absence of diabetic retinopathy or albuminuria was approximately 0.3 million. A substantial burden of CRI among persons with type 2 DM in the United States is likely due to renal parenchymal disease other than classic diabetic glomerulosclerosis. Approaches to screening renal disease in the type 2 DM population should incorporate assessment of GFR in addition to monitoring urine albumin excretion and funduscopic changes to ensure that individuals with type 2 DM and CRI not due to diabetic glomerulosclerosis will receive appropriate intervention.

                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                September 2012
                September 2012
                20 September 2012
                : 8
                : 9
                [1 ]Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
                [2 ]Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
                [3 ]Department of Biomedical Engineering and Computational Science, Aalto University, Espoo, Finland
                [4 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America
                [5 ]Endocrine Research Unit, Department of Endocrinology, Children's Hospital, Boston, Massachusetts, United States of America
                [6 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
                [7 ]Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, United Kingdom
                [8 ]Diabetes Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
                [9 ]Mater Misericordiae Hospital, Dublin, Ireland
                [10 ]Division of Nephrology and Hypertension, University of Miami, Miami, Florida, United States of America
                [11 ]Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [12 ]Institute of Clinical Medicine, Department of Internal Medicine, Biocenter Oulu and Clinical Research Center, University of Oulu, Oulu, Finland
                [13 ]Department of Medicine, University of Toronto, Toronto, Canada
                [14 ]Department of Clinical Sciences, Diabetes, and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden
                [15 ]Wellcome Trust Centre for Molecular Medicine, University of Dundee, Dundee, Scotland, United Kingdom
                [16 ]Computer Science, Eastern Michigan University, Ypsilanti, Michigan, United States of America
                [17 ]Division of Nephrology, Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America
                [18 ]Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
                [19 ]Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
                [20 ]Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland
                [21 ]Institute for Molecular Medicine Finland, Helsinki, Finland
                [22 ]Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland
                [23 ]Unit for Sports and Exercise Medicine, Institute of Clinical Medicine, University of Helsinki, Finland
                [24 ]South Ostrobothnia Central Hospital, Seinäjoki, Finland
                [25 ]Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, Madrid, Spain
                [26 ]Centre for Vascular Prevention, Danube-University Krems, Krems, Austria
                [27 ]Diabetes Endocrine Unit, Clinical Sciences Centre, Aintree University Hospital, University of Liverpool, Liverpool, United Kingdom
                [28 ]Institute of Life Sciences, Swansea University, Swansea, United Kingdom
                [29 ]Institute of Medical Science, University of Toronto, Toronto, Canada
                [30 ]Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
                [31 ]National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland, United States of America
                [32 ]Biostatics Division, The George Washington University, Washington, D.C., United States of America
                [33 ]Department of Medical Endocrinology, University Hospital of Copenhagen, Copenhagen, Denmark
                [34 ]Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
                [35 ]Steno Diabetes Center, Gentofte, Denmark
                [36 ]INSERM U872, Paris-Descartes University, Pierre and Marie Curie University, Paris, France
                [37 ]CHU Sart Tilman, Liège, Belgium
                [38 ]CHU Bordeaux, Bordeaux, France
                [39 ]AP-HP, Hôpital Bichat, Diabetology Endocrinology Nutrition, Paris, France
                [40 ]Université Paris Diderot, Sorbonne Paris Cité, UMR 738, Paris, France
                [41 ]INSERM, UMR872, Equipe 2, Centre de Recherche des Cordeliers, Paris, France
                [42 ]INSERM UMR_S 937, ICAN Institute for Cardiometabolism and Nutrition, Pierre and Marie Curie University, Paris, France
                [43 ]Complications of Diabetes Unit, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milano, Italy
                [44 ]Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
                [45 ]Department of Endocrinology, Metabolism, and Diabetes, Karolinska University Hospital, Stockholm, Sweden
                [46 ]Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden
                [47 ]Genetics Department, Bucharest University, Bucharest, Romania
                [48 ]University of Medicine and Pharmacy of Craiova, Craiova, Romania
                [49 ]“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
                [50 ]Diabetes Epidemiology and Clinical Research Section, NIDDK, Phoenix, Arizona, United States of America
                [51 ]Internal Medicine, Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America
                [52 ]CHU Poitiers–Endocrinology, University of Poitiers, Poitiers, France
                [53 ]INSERM CIC0802, CHU Poitiers, Poitiers, France
                [54 ]INSERM, U695 (Genetic Determinants of Type 2 Diabetes and Its Vascular Complications), Paris, France
                [55 ]Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Toronto, Canada
                [56 ]Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
                [57 ]Baker IDI Heart and Diabetes Institute, Melbourne, Australia
                [58 ]Regional Nephrology Unit, Belfast City Hospital, Belfast, United Kingdom
                University Hospital Regensburg, Germany
                Author notes

                JC Florez has received consulting honoraria from Novartis, Lilly, and Pfizer. M Kretzler received grant support from Hoffman La Roche and Fibrotech. P-H Groop has received lecture honorariums from Abbot, Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Novartis, Novo Nordisk, MSD, and research grants from Eli Lilly and Roche. P-H Groop is also an advisory board member of Boehringer Ingelheim and Novartis.

                Conceived and designed the experiments: AP Maxwell, JC Florez, JN Hirschhorn, P-H Groop, C Godson, F Martin, G Zerbini, M Marre, S Hadjadj, HF Gu, K Brismar, L Groop, NM Panduru, SC Bain, M Lajer, HM Colhoun, AD Paterson, D Waggott, SB Bull, M Kretzler. Performed the experiments: DA Savage, AJ McKnight, EJ Swan, C Guiducci, DB Mirel, A Taylor, C Godson, N Sandholm, M Parkkonen, J Söderlund, A Syreeni, P Lahermo, K Tryggvason, B He, A-M Österholm, AD Paterson, S Maestroni, S Hadjadj, M Marre, V Rigalleau, R Roussel, F Alhenc-Gelas, P Lefebvre, HF Gu, A Möllsten, T Gu, E Ahlqvist, M Ioana, M Stavarachi, D Cimponeriu, SM Hosseini, M Kretzler, RL Hanson. Analyzed the data: AJ McKnight, GJ McKay, EJ Swan, JC Florez, JN Hirschhorn, C Palmer, RM Salem, N Sandholm, C Forsblom, V-P Mäkinen, EP Brennan, F Martin, S Hadjadj, M Marre, V Rigalleau, R Roussel, F Alhenc-Gelas, P Lefebvre, D-A Tregouet, C Ladenvall, HA Deshmukh, AD Paterson, AP Boright, D Waggott, BJ Keller, H Huang, E Ahlqvist. Contributed reagents/materials/analysis tools: S Prior, SB Bull, GV Gill, AJ McKnight, AP Maxwell, T Isakova, WW Williams, N Sandholm, C Forsblom, V Harjutsalo, AJ Ahola, E Fagerholm, D Gordin, O Heikkilä, K Hietala, J Kytö, M Lehto, V-P Mäkinen, M Rosengård-Bärlund, LM Thorn, N Tolonen, M Saraheimo, A Soro-Paavonen, J Wadén, H Tikkanen, J Tuomilehto, P Lahermo, P-H Groop, J Pitkäniemi, C Sarti, K Tryggvason, B He, A-M Österholm, AD Paterson, DM Sadlier, G Zerbini, A Maestroni, HF Gu, A Möllsten, H Falhammar, E Ahlqvist, M Mota, EM, SC Bain, GV Gill, S Prior, M Lehto, L Tarnow, P Rossing, H-H Parving, HM Colhoun, HA Deshmukh, M Kretzler, RG Nelson, RL Hanson, R Lithovius, K Brismar. Wrote the paper: N Sandholm, RM Salem, AJ McKnight, EP Brennan, C Forsblom, T Isakova, GJ McKay, WW Williams, DM Sadlier, F Martin, JN Hirschhorn, C Godson, JC Florez, P-H Groop, AP Maxwell.

                ¶ Membership of the DCCT/EDIC Research Group is provided in Table S14.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 13
                United Kingdom: The Warren 3/UK GoKinD Study Group was jointly funded by Diabetes UK and the Juvenile Diabetes Research Foundation. EJ Swan is supported by Diabetes UK Studentship. The Golden Years cohort, established by GV Gill, AH Barnett, SC Bain, was funded by Diabetes UK. FinnDiane: The FinnDiane Study was supported by grants from the Folkhälsan Research Foundation, the Wilhelm and Else Stockmann Foundation, Liv och Hälsa Foundation, Helsinki University Central Hospital Research Funds (EVO), the Sigrid Juselius Foundation, the Signe and Arne Gyllenberg Foundation, Finska Läkaresällskapet, TEKES, the European Union's Seventh Framework Program (FP7/2007–2013) for the Innovative Medicine Initiative under grant agreement IMI/115006 (the SUMMIT consortium). V-P Mäkinen is supported by Orion-Farmos Research Foundation. Boston: The GENIE Consortium is supported by a US Ireland R&D partnership award funded by Science Foundation Ireland under Grant No. SFI/08/US/B1517, The Northern Ireland Research Development office, and NIH NIDDK R01 DK081923 to JN Hirschhorn, JC Florez, and P-H Groop. RM Salem was supported by a Juvenile Diabetes Research Foundation post doctoral fellowship (JDRF # 3-2011-70). Dublin: The ROI collection was supported by funding from the Health Research Board Ireland to Hugh R. Brady. Sweden (Stockholm and Umeå samples): Supported by Family Erling-Persson Foundation and Swedish Medical Research Council. Karolinska Institutet: Supported by Knut and Alice Wallengberg Foundation, Swedish Diabetes Society Foundation, Swedish Medical Research Council, and Novo Nordisk Foundation. SDR (Scania Diabetes Registry): The research at Lund University diabetes Centre was supported by the European Union's Seventh Framework Program (FP7/2007–2013) for the Innovative Medicine Initiative under grant agreement IMI/115006 (the SUMMIT consortium). E Ahlqvist was funded by a grant from ENGAGE. Romania: The RomDiane study was supported by Projects CNCSIS-PNCDI-II-RU-PD 133/2010, CNCSIS-PNCDI-II-RU-TD 66/2007, and CNCSIS–PNCDI-II-RU-PI-CE-ID 1194/2009. Steno: The study was made possible through support from the European Commission through contract QLG2-CT-2001-01669, the Danish Diabetes Association, and the Sehested Hansen Foundation. DCCT/EDIC: The DCCCT/EDIC Research Group is sponsored through research contracts from the National Institute of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institutes of Health. The Diabetes Control and Complications Trial (DCCT) and its follow-up the Epidemiology of Diabetes Interventions and Complications (EDIC) study were conducted by the DCCT/EDIC Research Group and supported by National Institute of Health grants and contracts and by the General Clinical Research Center Program, NCRR. SB Bull held a Canadian Institutes of Health Research (CIHR) Senior Investigator award (2002–7). AD Patterson holds a Canada Research Chair in the Genetics of Complex Diseases. This work has received support from National Institute of Diabetes and Digestive and Kidney Diseases Contract N01-DK-6-2204, National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-077510, and support from the Canadian Network of Centres of Excellence in Mathematics and from Genome Canada through the Ontario Genomics Institute. eQTL analysis in Pima Indians: This work was supported, in part, by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. France: GENEDIAB/GENESIS studies were supported by grants from the French Ministry of Health (Programmes Hospitaliers de Recherche Clinique), from the Société Francophone du Diabète, and from the Association Française des Diabétiques. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Gene Expression
                RNA interference
                Human Genetics
                Genome-Wide Association Studies
                Genetics of Disease
                Diabetic Endocrinology
                Diabetes Mellitus Type 1
                Chronic Kidney Disease



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