Cargando…

Genome-wide Association Study for AKI

KEY POINTS: Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI. BACKGROUND: Although common genetic risks for CKD are well established, genetic factors in...

Descripción completa

Detalles Bibliográficos
Autores principales: Bhatraju, Pavan K., Stanaway, Ian B., Palmer, Melody R., Menon, Rajasree, Schaub, Jennifer A., Menez, Steven, Srivastava, Anand, Wilson, F. Perry, Kiryluk, Krzysztof, Palevsky, Paul M., Naik, Abhijit S., Sakr, Sana S., Jarvik, Gail P., Parikh, Chirag R., Ware, Lorraine B., Ikizler, T. Alp, Siew, Edward D., Chinchilli, Vernon M., Coca, Steve G., Garg, Amit X., Go, Alan S., Kaufman, James S., Kimmel, Paul L., Himmelfarb, Jonathan, Wurfel, Mark M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Nephrology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371295/
https://www.ncbi.nlm.nih.gov/pubmed/37273234
http://dx.doi.org/10.34067/KID.0000000000000175
_version_ 1785078117910446080
author Bhatraju, Pavan K.
Stanaway, Ian B.
Palmer, Melody R.
Menon, Rajasree
Schaub, Jennifer A.
Menez, Steven
Srivastava, Anand
Wilson, F. Perry
Kiryluk, Krzysztof
Palevsky, Paul M.
Naik, Abhijit S.
Sakr, Sana S.
Jarvik, Gail P.
Parikh, Chirag R.
Ware, Lorraine B.
Ikizler, T. Alp
Siew, Edward D.
Chinchilli, Vernon M.
Coca, Steve G.
Garg, Amit X.
Go, Alan S.
Kaufman, James S.
Kimmel, Paul L.
Himmelfarb, Jonathan
Wurfel, Mark M.
author_facet Bhatraju, Pavan K.
Stanaway, Ian B.
Palmer, Melody R.
Menon, Rajasree
Schaub, Jennifer A.
Menez, Steven
Srivastava, Anand
Wilson, F. Perry
Kiryluk, Krzysztof
Palevsky, Paul M.
Naik, Abhijit S.
Sakr, Sana S.
Jarvik, Gail P.
Parikh, Chirag R.
Ware, Lorraine B.
Ikizler, T. Alp
Siew, Edward D.
Chinchilli, Vernon M.
Coca, Steve G.
Garg, Amit X.
Go, Alan S.
Kaufman, James S.
Kimmel, Paul L.
Himmelfarb, Jonathan
Wurfel, Mark M.
author_sort Bhatraju, Pavan K.
collection PubMed
description KEY POINTS: Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI. BACKGROUND: Although common genetic risks for CKD are well established, genetic factors influencing risk for AKI in hospitalized patients are poorly understood. METHODS: We conducted a genome-wide association study in 1369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI Study; a multiethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities, and kidney function before hospitalization. We then completed functional annotation of top-performing variants for AKI using single-cell RNA sequencing data from kidney biopsies in 12 patients with AKI and 18 healthy living donors from the Kidney Precision Medicine Project. RESULTS: No genome-wide significant associations with AKI risk were found in Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (P < 5×10(−8)). The top two variants with the strongest association with AKI mapped to the dispatched resistance-nodulation-division (RND) transporter family member 1 (DISP1) gene and toll-like receptor 5 (TLR5) gene locus, rs17538288 (odds ratio, 1.55; 95% confidence interval, 1.32 to 182; P = 9.47×10(−8)) and rs7546189 (odds ratio, 1.53; 95% confidence interval, 1.30 to 1.81; P = 4.60×10(−7)). In comparison with kidney tissue from healthy living donors, kidney biopsies in patients with AKI showed differential DISP1 expression in proximal tubular epithelial cells (adjusted P = 3.9×10(−2)) and thick ascending limb of the loop of Henle (adjusted P = 8.7×10(−3)) and differential TLR5 gene expression in thick ascending limb of the loop of Henle (adjusted P = 4.9×10(−30)). CONCLUSIONS: AKI is a heterogeneous clinical syndrome with various underlying risk factors, etiologies, and pathophysiology that may limit the identification of genetic variants. Although no variants reached genome-wide significance, we report two variants in the intergenic region between DISP1 and TLR5, suggesting this region as a novel risk for AKI susceptibility.
format Online
Article
Text
id pubmed-10371295
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Society of Nephrology
record_format MEDLINE/PubMed
spelling pubmed-103712952023-08-03 Genome-wide Association Study for AKI Bhatraju, Pavan K. Stanaway, Ian B. Palmer, Melody R. Menon, Rajasree Schaub, Jennifer A. Menez, Steven Srivastava, Anand Wilson, F. Perry Kiryluk, Krzysztof Palevsky, Paul M. Naik, Abhijit S. Sakr, Sana S. Jarvik, Gail P. Parikh, Chirag R. Ware, Lorraine B. Ikizler, T. Alp Siew, Edward D. Chinchilli, Vernon M. Coca, Steve G. Garg, Amit X. Go, Alan S. Kaufman, James S. Kimmel, Paul L. Himmelfarb, Jonathan Wurfel, Mark M. Kidney360 Original Investigation KEY POINTS: Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI. BACKGROUND: Although common genetic risks for CKD are well established, genetic factors influencing risk for AKI in hospitalized patients are poorly understood. METHODS: We conducted a genome-wide association study in 1369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI Study; a multiethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities, and kidney function before hospitalization. We then completed functional annotation of top-performing variants for AKI using single-cell RNA sequencing data from kidney biopsies in 12 patients with AKI and 18 healthy living donors from the Kidney Precision Medicine Project. RESULTS: No genome-wide significant associations with AKI risk were found in Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (P < 5×10(−8)). The top two variants with the strongest association with AKI mapped to the dispatched resistance-nodulation-division (RND) transporter family member 1 (DISP1) gene and toll-like receptor 5 (TLR5) gene locus, rs17538288 (odds ratio, 1.55; 95% confidence interval, 1.32 to 182; P = 9.47×10(−8)) and rs7546189 (odds ratio, 1.53; 95% confidence interval, 1.30 to 1.81; P = 4.60×10(−7)). In comparison with kidney tissue from healthy living donors, kidney biopsies in patients with AKI showed differential DISP1 expression in proximal tubular epithelial cells (adjusted P = 3.9×10(−2)) and thick ascending limb of the loop of Henle (adjusted P = 8.7×10(−3)) and differential TLR5 gene expression in thick ascending limb of the loop of Henle (adjusted P = 4.9×10(−30)). CONCLUSIONS: AKI is a heterogeneous clinical syndrome with various underlying risk factors, etiologies, and pathophysiology that may limit the identification of genetic variants. Although no variants reached genome-wide significance, we report two variants in the intergenic region between DISP1 and TLR5, suggesting this region as a novel risk for AKI susceptibility. American Society of Nephrology 2023-06-05 /pmc/articles/PMC10371295/ /pubmed/37273234 http://dx.doi.org/10.34067/KID.0000000000000175 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Investigation
Bhatraju, Pavan K.
Stanaway, Ian B.
Palmer, Melody R.
Menon, Rajasree
Schaub, Jennifer A.
Menez, Steven
Srivastava, Anand
Wilson, F. Perry
Kiryluk, Krzysztof
Palevsky, Paul M.
Naik, Abhijit S.
Sakr, Sana S.
Jarvik, Gail P.
Parikh, Chirag R.
Ware, Lorraine B.
Ikizler, T. Alp
Siew, Edward D.
Chinchilli, Vernon M.
Coca, Steve G.
Garg, Amit X.
Go, Alan S.
Kaufman, James S.
Kimmel, Paul L.
Himmelfarb, Jonathan
Wurfel, Mark M.
Genome-wide Association Study for AKI
title Genome-wide Association Study for AKI
title_full Genome-wide Association Study for AKI
title_fullStr Genome-wide Association Study for AKI
title_full_unstemmed Genome-wide Association Study for AKI
title_short Genome-wide Association Study for AKI
title_sort genome-wide association study for aki
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371295/
https://www.ncbi.nlm.nih.gov/pubmed/37273234
http://dx.doi.org/10.34067/KID.0000000000000175
work_keys_str_mv AT bhatrajupavank genomewideassociationstudyforaki
AT stanawayianb genomewideassociationstudyforaki
AT palmermelodyr genomewideassociationstudyforaki
AT menonrajasree genomewideassociationstudyforaki
AT schaubjennifera genomewideassociationstudyforaki
AT menezsteven genomewideassociationstudyforaki
AT srivastavaanand genomewideassociationstudyforaki
AT wilsonfperry genomewideassociationstudyforaki
AT kirylukkrzysztof genomewideassociationstudyforaki
AT palevskypaulm genomewideassociationstudyforaki
AT naikabhijits genomewideassociationstudyforaki
AT sakrsanas genomewideassociationstudyforaki
AT jarvikgailp genomewideassociationstudyforaki
AT parikhchiragr genomewideassociationstudyforaki
AT warelorraineb genomewideassociationstudyforaki
AT ikizlertalp genomewideassociationstudyforaki
AT siewedwardd genomewideassociationstudyforaki
AT chinchillivernonm genomewideassociationstudyforaki
AT cocasteveg genomewideassociationstudyforaki
AT gargamitx genomewideassociationstudyforaki
AT goalans genomewideassociationstudyforaki
AT kaufmanjamess genomewideassociationstudyforaki
AT kimmelpaull genomewideassociationstudyforaki
AT himmelfarbjonathan genomewideassociationstudyforaki
AT wurfelmarkm genomewideassociationstudyforaki