期刊
DIABETES
卷 65, 期 3, 页码 803-817出版社
AMER DIABETES ASSOC
DOI: 10.2337/db15-1313
关键词
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资金
- National Foundation for Alzheimer's disease and related disorders
- Institut Pasteur de Lille
- Centre National de Genotypage
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante
- MGEN
- Institut de la Longevite
- Agence Francaise de Securite Sanitaire des Produits de Sante
- Aquitaine and Bourgogne Regional Councils
- Fondation de France
- French Ministry of Research/INSERM Cohortes et collections de donnees biologiques programme
- Eisai
- Prognomix, Inc.
- Genome Quebec
- Canadian Institutes of Health Research (CIHR)
- Les Laboratoires Servier, France
- National Health and Medical Research Council of Australia
- National Institutes of Health (NIH) [N01-AG-1-2100, HHSN271201200022C]
- National Institute on Aging Intramural Research Program
- Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- NIH [R01-AG-18728, R01-HL-088119, U01-GM-074518-04, U01-HL0-72515-06, U01-HL0-84756, K12-RR0-23250, HHSN268200625226C, UL1-RR0-25005, 2R01LM0- 10098, R01-DK0-76077, DK0-87635]
- Baltimore Veterans Administration Medical Center Geriatric Research Education and Clinical Center
- Paul Beeson Physician Faculty Scholars in Aging Research Program
- Mid-Atlantic Nutrition Obesity Research Center [P30-DK0-72488]
- National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]
- National Human Genome Research Institute [U01-HG0-04402]
- NIH Roadmap for Medical Research
- Emmy Noether Programme of the German Research Foundation [KO 3598/2-1]
- Intramural Research Program of the NIH, National Institute on Aging
- National Center for Research Resources [M01-RR-00425]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK-063491]
- GlaxoSmithKline
- Faculty of Biology and Medicine of Lausanne
- Swiss National Science Foundation [33CSCO-122661, 33CM30-124087, 310030_146490]
- Medical Research Council U.K.
- Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302]
- Medical Research Council
- Cancer Research U.K.
- Baden-Wurttemberg State Ministry of Science, Research and Arts
- German Federal Ministry of Education and Research [01ET0717]
- CHANCES (Consortium on Health and Ageing: Network of Cohorts in Europe and the United States) project [242244]
- Medical Research Council [MC_U106179471]
- Wellcome Trust
- National Heart, Lung and Blood Institute Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc. [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Boston University School of Medicine Department of Medicine and Boston Medical Center
- Dr. Robert Pfleger-Stiftung
- MSD Stipend Diabetes
- University Hospital of Regensburg
- KfH Stiftung Praventivmedizin e.V.
- Else Kroner-Fresenius-Stiftung [2012_A147]
- University Hospital Regensburg
- Else Kroner-Fresenius Stiftung [2012_A147, P48/08//A11/08]
- Wellcome Trust [WT098051, WT091310]
- European Union [257082, HEALTH-F5-2011-282510, LSHG-CT-2006-018947]
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- Regensburg University Medical Center, Germany
- F4 by the University of Ulm, Germany
- Helmholtz Zentrum Munchen
- German Research Center for Environmental Health
- German Federal Ministry of Education and Research
- State of Bavaria
- University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center
- Netherlands Organization of Scientific Research NWO [175.010.2007.006]
- Economic Structure Enhancing Fund (FES) of the Dutch government
- Ministry of Economic Affairs
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- Northern Netherlands Collaboration of Provinces
- Province of Groningen
- University Medical Center Groningen
- University of Groningen
- Dutch Kidney Foundation
- Dutch Diabetes Research Foundation
- Ministry of Health and Department of Educational Assistance
- University and Research of the Autonomous Province of Bolzano
- South Tyrolean Sparkasse Foundation
- Dutch Kidney Foundation [E033]
- EU [FP-6 LSHM CT 2006 037697]
- Netherlands Organisation for Health Research and Development NWO-Groot grant [175.010.2007.006]
- NWO VENI [916.761.70]
- ZonMw grant [90.700.441]
- Dutch Inter University Cardiology Institute Netherlands (ICIN)
- Kamillo Eisner Stiftung
- Genomics of Lipidassociated Disorders (GOLD) of the Austrian Genome Research Programme GEN-AU
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- network Greifswald Approach to Individualized Medicine (GANI_MED) - Federal Ministry of Education and Research [03IS2061A]
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg-West Pomerania
- Lausanne University Hospital
- Geneva University Hospital
- Bern University Hospital, Switzerland
- Swiss School of Public Health Plus (SSPH+)
- National Institute of General Medical Sciences (NIGMS) [RC2-GM092318]
- Electronic Medical Records and Genomics (eMERGE) Network
- National Human Genome Research Institute
- NIGMS [U01-HG04603]
- European Community [305608]
- [R01-HL0-87641]
- [R01-HL-9367]
- [R01-HL0-86694]
- [2R01-069321]
- [N01-HC-85079]
- [N01-HC-85080]
- [N01-HC-85081]
- [N01-HC-85082]
- [N01-HC-85083]
- [N01-HC-85084]
- [N01-HC-85085]
- [N01-HC-85086]
- [N01-HC-35129]
- [N01-HC-15103]
- [N01-HC-55222]
- [N01-HC-75150]
- [N01-HC-45133]
- [U01-HL0-80295]
- [R01-HL0-87652]
- Medical Research Council [MC_U106179471, MC_PC_U127561128, MC_UU_12015/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10135] Funding Source: researchfish
- MRC [MC_UU_12015/1, MC_PC_U127561128] Funding Source: UKRI
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 x 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 x 10(-7)) and 13% for RAB38/CTSC (P = 5.8 x 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
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