Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 ( HSD17B14 ) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

Autor:	Mychaleckyj JC; Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia., Valo E; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland., Ichimura T; Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts., Ahluwalia TS; Steno Diabetes Center Copenhagen, Copenhagen, Denmark., Dina C; Université de Nantes, CNRS INSERM, L'institut du thorax, Nantes, France., Miller RG; Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania., Shabalin IG; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia., Gyorgy B; INSERM UMRS1166, Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France., Cao J; Genetics & Genome Biology Research Institute, SickKids Hospital, Toronto, Ontario, Canada., Onengut-Gumuscu S; Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia., Satake E; Research Division, Joslin Diabetes Center, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts., Smiles AM; Research Division, Joslin Diabetes Center, Boston, Massachusetts., Haukka JK; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland., Tregouet DA; INSERM UMRS1166, Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France.; Université de Bordeaux, INSERM, Bordeaux Population Health, Bordeaux U1219, France., Costacou T; Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania., O'Neil K; Research Division, Joslin Diabetes Center, Boston, Massachusetts., Paterson AD; Genetics & Genome Biology Research Institute, SickKids Hospital, Toronto, Ontario, Canada., Forsblom C; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland., Keenan HA; Research Division, Joslin Diabetes Center, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts., Pezzolesi MG; Research Division, Joslin Diabetes Center, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.; Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah., Pragnell M; JDRF International, New York, New York., Galecki A; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan., Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia., Sandholm N; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland., Klein R; Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Klein BE; Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin., Susztak K; Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania., Orchard TJ; Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania., Korstanje R; The Jackson Laboratory, Bar Harbor, Maine., King GL; Research Division, Joslin Diabetes Center, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts., Hadjadj S; INSERM CIC 1402 and U 1082, Poitiers, France.; Department of Endocrinology, L'institut du thorax, INSERM, CNRS, Centre Hospitalier Universitaire de Nantes, Nantes, France., Rossing P; Steno Diabetes Center Copenhagen, Copenhagen, Denmark.; University of Copenhagen, Copenhagen, Denmark., Bonventre JV; Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts., Groop PH; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland.; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia., Warram JH; Research Division, Joslin Diabetes Center, Boston, Massachusetts., Krolewski AS; Research Division, Joslin Diabetes Center, Boston, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2021 Oct; Vol. 32 (10), pp. 2634-2651. Date of Electronic Publication: 2021 Jul 14.
DOI:	10.1681/ASN.2020101457
Abstrakt:	Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort ( n =2372/1115 events all cohorts) and replicating in two retrospective case-control studies ( n =1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results: Protein coding variants in the hydroxysteroid 17- β dehydrogenase 14 gene ( HSD17B14 ), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance ( n =4196; P value=3.3 × 10 -7 ). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. Conclusions: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development. (Copyright © 2021 by the American Society of Nephrology.)
Databáze:	MEDLINE
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