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

Harvard

Mychaleckyj, JC, Valo, E, Ichimura, T, Ahluwalia, TS, Dina, C, Miller, RG, Shabalin, IG, Gyorgy, B, Cao, JJ, Onengut-Gumuscu, S, Satake, E, Smiles, AM, Haukka, JK, Tregouet, DA, Costacou, T, O’Neil, K, Paterson, AD, Forsblom, C, Keenan, HA, Pezzolesi, MG, Pragnell, M, Galecki, A, Rich, SS, Sandholm, N, Klein, R, Klein, BE, Susztak, K, Orchard, TJ, Korstanje, R, King, GL, Hadjadj, S, Rossing, P, Bonventre, JV, Groop, PH, Warram, JH & Krolewski, AS 2021, 'Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes', Journal of the American Society of Nephrology, vol. 32, no. 10, pp. 2634-2651. https://doi.org/10.1681/ASN.2020101457

APA

Mychaleckyj, J. C., Valo, E., Ichimura, T., Ahluwalia, T. S., Dina, C., Miller, R. G., Shabalin, I. G., Gyorgy, B., Cao, J. J., Onengut-Gumuscu, S., Satake, E., Smiles, A. M., Haukka, J. K., Tregouet, D. A., Costacou, T., O’Neil, K., Paterson, A. D., Forsblom, C., Keenan, H. A., ... Krolewski, A. S. (2021). Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes. Journal of the American Society of Nephrology, 32(10), 2634-2651. https://doi.org/10.1681/ASN.2020101457

Vancouver

Mychaleckyj JC, Valo E, Ichimura T, Ahluwalia TS, Dina C, Miller RG et al. Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes. Journal of the American Society of Nephrology. 2021;32(10):2634-2651. https://doi.org/10.1681/ASN.2020101457

Author

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. / Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes. In: Journal of the American Society of Nephrology. 2021 ; Vol. 32, No. 10. pp. 2634-2651.

Bibtex

@article{ff2a46c8b8da42f8911829e7a7b0ecdc,

title = "Association of coding variants in hydroxysteroid 17-beta dehydrogenase 14 (HSD17B14) with reduced progression to end stage kidney disease in type 1 diabetes",

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 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.",

author = "Mychaleckyj, {Josyf C.} and Erkka Valo and Takaharu Ichimura and Ahluwalia, {Tarunveer S.} and Christian Dina and Miller, {Rachel G.} and Shabalin, {Ivan G.} and Beata Gyorgy and Cao, {Jing Jing} and Suna Onengut-Gumuscu and Eiichiro Satake and Smiles, {Adam M.} and Haukka, {Jani K.} and Tregouet, {David Alexandre} and Tina Costacou and Kristina O{\textquoteright}Neil and Paterson, {Andrew D.} and Carol Forsblom and Keenan, {Hillary A.} and Pezzolesi, {Marcus G.} and Marlon Pragnell and Andrzej Galecki and Rich, {Stephen S.} and Niina Sandholm and Ronald Klein and Klein, {Barbara E.} and Katalin Susztak and Orchard, {Trevor J.} and Ron Korstanje and King, {George L.} and Samy Hadjadj and Peter Rossing and Bonventre, {Joseph V.} and Groop, {Per Henrik} and Warram, {James H.} and Krolewski, {Andrzej S.}",

note = "Publisher Copyright: {\textcopyright} 2021 by the American Society of Nephrology.",

year = "2021",

doi = "10.1681/ASN.2020101457",

language = "English",

volume = "32",

pages = "2634--2651",

journal = "Journal of the American Society of Nephrology : JASN",

issn = "1046-6673",

publisher = "American Society of Nephrology",

number = "10",

}

RIS

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.

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

Forskning