Josyf C Mychaleckyj1, Erkka Valo2,3,4, Takaharu Ichimura5, Tarunveer S Ahluwalia6, Christian Dina7, Rachel G Miller8, Ivan G Shabalin9, Beata Gyorgy10, JingJing Cao11, Suna Onengut-Gumuscu12, Eiichiro Satake13,14, Adam M Smiles13, Jani K Haukka2,3,4, David-Alexandre Tregouet10,15, Tina Costacou8, Kristina O'Neil13, Andrew D Paterson11, Carol Forsblom2,3,4, Hillary A Keenan13,14, Marcus G Pezzolesi13,14,16, Marlon Pragnell17, Andrzej Galecki18, Stephen S Rich12, Niina Sandholm2,3,4, Ronald Klein19, Barbara E Klein19, Katalin Susztak20, Trevor J Orchard8, Ron Korstanje21, George L King13,14, Samy Hadjadj22,23, Peter Rossing24,6, Joseph V Bonventre5, Per-Henrik Groop2,25,3,4, James H Warram13, Andrzej S Krolewski26,14. 1. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia jcm6t@virginia.edu. 2. Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland. 3. Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 4. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland. 5. Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts. 6. Steno Diabetes Center Copenhagen, Copenhagen, Denmark. 7. Université de Nantes, CNRS INSERM, L'institut du thorax, Nantes, France. 8. Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania. 9. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia. 10. INSERM UMRS1166, Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France. 11. Genetics & Genome Biology Research Institute, SickKids Hospital, Toronto, Ontario, Canada. 12. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. 13. Research Division, Joslin Diabetes Center, Boston, Massachusetts. 14. Department of Medicine, Harvard Medical School, Boston, Massachusetts. 15. Université de Bordeaux, INSERM, Bordeaux Population Health, Bordeaux U1219, France. 16. Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah. 17. JDRF International, New York, New York. 18. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. 19. Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. 20. Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania. 21. The Jackson Laboratory, Bar Harbor, Maine. 22. INSERM CIC 1402 and U 1082, Poitiers, France. 23. Department of Endocrinology, L'institut du thorax, INSERM, CNRS, Centre Hospitalier Universitaire de Nantes, Nantes, France. 24. University of Copenhagen, Copenhagen, Denmark. 25. Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia. 26. Research Division, Joslin Diabetes Center, Boston, Massachusetts jcm6t@virginia.edu.
Abstract
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.
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.
Authors: Florian Braun; Nicole Bertoletti; Gabriele Möller; Jerzy Adamski; Torsten Steinmetzer; Mohamed Salah; Ahmed S Abdelsamie; Chris J van Koppen; Andreas Heine; Gerhard Klebe; Sandrine Marchais-Oberwinkler Journal: J Med Chem Date: 2016-11-18 Impact factor: 7.446
Authors: Rany M Salem; Jennifer N Todd; Niina Sandholm; Joanne B Cole; Wei-Min Chen; Darrell Andrews; Marcus G Pezzolesi; Paul M McKeigue; Linda T Hiraki; Chengxiang Qiu; Viji Nair; Chen Di Liao; Jing Jing Cao; Erkka Valo; Suna Onengut-Gumuscu; Adam M Smiles; Stuart J McGurnaghan; Jani K Haukka; Valma Harjutsalo; Eoin P Brennan; Natalie van Zuydam; Emma Ahlqvist; Ross Doyle; Tarunveer S Ahluwalia; Maria Lajer; Maria F Hughes; Jihwan Park; Jan Skupien; Athina Spiliopoulou; Andrew Liu; Rajasree Menon; Carine M Boustany-Kari; Hyun M Kang; Robert G Nelson; Ronald Klein; Barbara E Klein; Kristine E Lee; Xiaoyu Gao; Michael Mauer; Silvia Maestroni; Maria Luiza Caramori; Ian H de Boer; Rachel G Miller; Jingchuan Guo; Andrew P Boright; David Tregouet; Beata Gyorgy; Janet K Snell-Bergeon; David M Maahs; Shelley B Bull; Angelo J Canty; Colin N A Palmer; Lars Stechemesser; Bernhard Paulweber; Raimund Weitgasser; Jelizaveta Sokolovska; Vita Rovīte; Valdis Pīrāgs; Edita Prakapiene; Lina Radzeviciene; Rasa Verkauskiene; Nicolae Mircea Panduru; Leif C Groop; Mark I McCarthy; Harvest F Gu; Anna Möllsten; Henrik Falhammar; Kerstin Brismar; Finian Martin; Peter Rossing; Tina Costacou; Gianpaolo Zerbini; Michel Marre; Samy Hadjadj; Amy J McKnight; Carol Forsblom; Gareth McKay; Catherine Godson; A Peter Maxwell; Matthias Kretzler; Katalin Susztak; Helen M Colhoun; Andrzej Krolewski; Andrew D Paterson; Per-Henrik Groop; Stephen S Rich; Joel N Hirschhorn; Jose C Florez Journal: J Am Soc Nephrol Date: 2019-09-19 Impact factor: 14.978
Authors: Parker C Wilson; Haojia Wu; Yuhei Kirita; Kohei Uchimura; Nicolas Ledru; Helmut G Rennke; Paul A Welling; Sushrut S Waikar; Benjamin D Humphreys Journal: Proc Natl Acad Sci U S A Date: 2019-09-10 Impact factor: 11.205