Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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 (n52372/1115 events all cohorts) and replicating in two retrospective case-control studies (n51072 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-b dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n54196; P value53.3 3 1027). 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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of the American Society of Nephrology |
| Vol/bind | 32 |
| Udgave nummer | 10 |
| Sider (fra-til) | 2634-2651 |
| Antal sider | 18 |
| ISSN | 1046-6673 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
J.V. Bonventre reports being cofounder of Goldfinch Bio and is coinventor with T. Ichimura on KIM-1 patents assigned to Partners Healthcare; being a consultant for Aldeyra, Cerespir, Merck, Mitobridge, and PTC; ownership interest in Amazon; ownership equity in Avexxin, Dicerna, DXNow, Goldfinch, Goldilocks, Innoviva, MediBeacon, Medssenger, Pacific Biosciences, Rubius, Sensor-Kinesis, Sentien, Theravance, and Verinano; consultancy agreements with Aditum, Citrine, Janssen, MediBeacon, Praxis, and Serepta; scientific advisor or membership as Editor of Seminars in Nephrology, the Advisory Board of the Northwest Kidney Center, and Angion; and was supported by National Institutes of Health (NIH)-National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants: R37 DK39773, R01 DK072381, and NCATS/NIDDK UG TR002155. C. Forsblom reports Scientific Advisor or Membership as a member of the Advisory Board for Acta Diabetologica, and the Editorial Board of the Journal of Diabetes Research; and Other Interests/Relationships as Secretary of the Board of the Finnish Diabetes Research Society. P. Groop reports consultancy agreements with Bayer and Boehringer Ingelheim; research funding from Eli Lilly, Roche (.5 years ago); honoraria from lecture fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Genzyme, Medscape, MSD, Mundi-pharma, Novartis, Novo Nordisk, PeerVoice, Sanofi, and SCIARC; scientific advisor or membership as Member of Advisory Boards for Astellas, AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Medscape, MSD, Mundipharma, Nestlé, Novartis, Novo Nordisk, and Sanofi; and other interests/relationships as Chairman of the Board of the Signe and Ane Gyl-lenberg Foundation, Chairman of the Board of the Board of the Finnish Kidney Disease Registry, and Member of the Board of the European Association for the Study of Diabetes. R. Korstanje reports Scientific Advisor or Membership with the Alport Syndrome Foundation. A. Krolewski reports current employment with Joslin Diabetes Center. K. O’Neil is employed by Joslin Diabetes Center. S. Rich reports Scientific Advisor or Membership with the American Diabetes Association (Diabetes Care Associate Editor), and the National Human Genome Research Institute National Advisory Board. P. Rossing reports Research Funding from AstraZeneca and Novo Nordisk; Honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk, all honoraria to institution; and Scientific Advisor or Membership with Astellas, Astra Zeneca, Bayer, Gilead, MSD, Mundipharma, and Novo Nordisk, all honoraria to institution. E. Satake reports employment with Joslin Diabetes Center; and Research Funding from Novo Nordisk and the Sunstar Foundation. I. Shabalin reports employment with and ownership interest in IDEAYA Biosciences. K. Susztak reports Consultancy Agreements with Astra Zeneca, Bayer, Jnana, Maze, and Pfizer; Ownership Interest in Jnana; Research Funding from Bayer, Boehringer Ingelheim, Calico, Gilead, GSK, Lilly, Maze, Merck, Novartis, Novo Nordisk, and Regeneron; Honoraria from AstraZeneca, Bayer, Jnana, and Maze; and Scientific Advisor or Membership via Editorial board for Kidney International, the Journal of Clinical Investigation, Cell Metabolism, EBioMedicine, the Journal of American Society of Nephrology, and Jnana. S. Hadjadj reports consultancy agreements with Lilly, Boehringer, and Abbott; research funding from Abbott, Novo Nordisk, Novartis, and DinnoSanté; honoraria from Lilly, Boehringer, Abbott, Servier, Sanofi, Novo Nordisk, Bayer, AstraZeneca, and Mundi Pharma; and scientific advisor or membership with Valbiotis. A. Galecki reports scientific advisor or membership with Open Journal of Applied Statistics and was supported by National Institute of Aging Claude D. Pepper Older Americans Independence Center grant AG08808. All remaining authors have nothing to disclose.
Funding Information:
This study was supported by a JDRF grant (3-SRA-2018-529-M-B) to J.C. Mychaleckyj, J.V. Bonventre, R. Klein, and A.S. Krolewski; a JDRF grant (17-2013-8) for DNCRI subproject “Search for genes determining time to onset of ESRD in type 1 diabetes patients with proteinuria” to S. Hadjadj, P. Ross-ing, P.-H. Groop, and A.S. Krolewski; JDRF grants (6-2010-550, 1-2008-1018) to A.S. Krolewski; National Institutes of Health grant DK-041526 to A.S. Krolewski; and the Joslin Diabetes Research Center grant P30 DK036836. The FinnDiane study was funded by JDRF (17-2013-7), the Novo Nordisk Foundation (OC0013659), the Academy of Finland (275614, 299200, and 316664), Folkh€alsan Research Foundation (2019), the Wilhelm and Else Stockmann Foundation (2018), and Helsinki University Hospital Research Funds (TYH2018207) to E. Valo, N. Sandholm, C. Forsblom, and P.-H. Groop. The Pittsburgh Epidemiology of Diabetes Complications study was supported by NIDDK grant DK34818. The Wisconsin Epidemiologic Study of Diabetic Retinopathy study was funded by NEI EY016379.
Funding Information:
The Pittsburgh Epidemiology of Diabetes Complications (EDC) study gratefully acknowledges the financial support of the Rossi Memorial Fund.
Publisher Copyright:
© 2021 by the American Society of Nephrology.
ID: 302043755