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

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, The Jackson Laboratory
George King
Samy Hadjadj
Peter Rossing
Joseph Bonventre
Per-Henrik Groop
James Warram
Andrzej Krolewski


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 end stage kidney disease (ESKD) in individuals with type 1 diabetes at advanced kidney disease stage.

METHODS: Gene-based exome array analysis of 15,449 genes in 5 large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time-to-ESKD, testing the top gene in a 6th cohort (N=2,372/1,115 events all cohorts) and replicating in two retrospective case-control studies (N=1,072 cases, 752 controls). Deep resequencing of the top associated gene in 5 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-beta dehydrogenase 14 gene (