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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Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes. / Mychaleckyj, Josyf C.; Valo, Erkka; Ichimura, Takaharu; Ahluwalia, Tarunveer S.; Dina, Christian; Miller, Rachel G.; Shabalin, Ivan G.; Gyorgy, Beata; Cao, Jing Jing; Onengut-Gumuscu, Suna; Satake, Eiichiro; Smiles, Adam M.; Haukka, Jani K.; Tregouet, David Alexandre; Costacou, Tina; O’Neil, Kristina; Paterson, Andrew D.; Forsblom, Carol; Keenan, Hillary A.; Pezzolesi, Marcus G.; Pragnell, Marlon; Galecki, Andrzej; Rich, Stephen S.; Sandholm, Niina; Klein, Ronald; Klein, Barbara E.; Susztak, Katalin; Orchard, Trevor J.; Korstanje, Ron; King, George L.; Hadjadj, Samy; Rossing, Peter; Bonventre, Joseph V.; Groop, Per Henrik; Warram, James H.; Krolewski, Andrzej S.
In: Journal of the American Society of Nephrology, Vol. 32, No. 10, 2021, p. 2634-2651.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes
AU - Mychaleckyj, Josyf C.
AU - Valo, Erkka
AU - Ichimura, Takaharu
AU - Ahluwalia, Tarunveer S.
AU - Dina, Christian
AU - Miller, Rachel G.
AU - Shabalin, Ivan G.
AU - Gyorgy, Beata
AU - Cao, Jing Jing
AU - Onengut-Gumuscu, Suna
AU - Satake, Eiichiro
AU - Smiles, Adam M.
AU - Haukka, Jani K.
AU - Tregouet, David Alexandre
AU - Costacou, Tina
AU - O’Neil, Kristina
AU - Paterson, Andrew D.
AU - Forsblom, Carol
AU - Keenan, Hillary A.
AU - Pezzolesi, Marcus G.
AU - Pragnell, Marlon
AU - Galecki, Andrzej
AU - Rich, Stephen S.
AU - Sandholm, Niina
AU - Klein, Ronald
AU - Klein, Barbara E.
AU - Susztak, Katalin
AU - Orchard, Trevor J.
AU - Korstanje, Ron
AU - King, George L.
AU - Hadjadj, Samy
AU - Rossing, Peter
AU - Bonventre, Joseph V.
AU - Groop, Per Henrik
AU - Warram, James H.
AU - Krolewski, Andrzej S.
N1 - Publisher Copyright: © 2021 by the American Society of Nephrology.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1681/ASN.2020101457
DO - 10.1681/ASN.2020101457
M3 - Journal article
C2 - 34261756
AN - SCOPUS:85116559147
VL - 32
SP - 2634
EP - 2651
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 10
ER -
ID: 302043755