Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Authors' Reply

    Research output: Contribution to journalComment/debateResearchpeer-review

  4. Assessment of Perfusion and Oxygenation of the Human Renal Cortex and Medulla by Quantitative MRI during Handgrip Exercise

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Cardiovascular autonomic neuropathy and the impact on progression of diabetic kidney disease in type 1 diabetes

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Josyf Mychaleckyj
  • Erkka Valo
  • Takaharu Ichimura
  • Tarunveer Ahluwalia
  • Christian Dina
  • Rachel Miller
  • Ivan Shabalin
  • Beata Gyorgy
  • JingJing Cao
  • Suna Onengut-Gumuscu
  • Eiichiro Satake
  • Adam Smiles
  • Jani Haukka
  • David-Alexandre Tregouet
  • Tina Costacou
  • Kristina O'Neil
  • Andrew Paterson
  • Carol Forsblom
  • Hillary Keenan
  • Marcus Pezzolesi
  • Marlon Pragnell
  • Andrzej Galecki
  • Stephen Rich
  • Niina Sandholm
  • Ronald Klein
  • Barbara Klein
  • Katalin Susztak
  • Trevor Orchard
  • Ron Korstanje
  • George King
  • Samy Hadjadj
  • Peter Rossing
  • Joseph Bonventre
  • Per-Henrik Groop
  • James Warram
  • Andrzej Krolewski
View graph of relations

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.

Original languageEnglish
JournalJournal of the American Society of Nephrology : JASN
Volume32
Issue number10
Pages (from-to)2634-2651
Number of pages18
ISSN1046-6673
DOIs
Publication statusPublished - Oct 2021

ID: 66943275