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

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  • 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
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftJournal of the American Society of Nephrology : JASN
Vol/bind32
Udgave nummer10
Sider (fra-til)2634-2651
Antal sider18
ISSN1046-6673
DOI
StatusUdgivet - okt. 2021

ID: 66943275