@article {1603874,
	title = {Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes},
	journal = {J Am Soc Nephrol},
	year = {2021},
	month = {2021 Jul 14},
	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 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 (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (N=4,196; p-value=3.3x10-7). 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 chronic kidney disease-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.},
	issn = {1533-3450},
	doi = {10.1681/ASN.2020101457},
	author = {Mychaleckyj, Josyf and Valo, Erkka and Ichimura, Takaharu and Ahluwalia, Tarunveer and Dina, Christian and Rachel Miller and Shabalin, Ivan and Gyorgy, Beata and Cao, Jingjing and Onengut-Gumuscu, Suna and Satake, Eiichiro and Smiles, Adam and Haukka, Jani and Tregouet, David-Alexandre and Costacou, Tina and O{\textquoteright}Neil, Kristina and Paterson, Andrew and Forsblom, Carol and Keenan, Hillary and Pezzolesi, Marcus and Pragnell, Marlon and Galecki, Andrzej and Rich, Stephen and Sandholm, Niina and Klein, Ronald and Klein, Barbara and Susztak, Katalin and Orchard, Trevor and Korstanje, Ron and King, George and Hadjadj, Samy and Rossing, Peter and Bonventre, Joseph and Groop, Per-Henrik and Warram, James and Krolewski, Andrzej}
}
