抄録
Background Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. Methods We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. Results Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. Conclusions Common variants in KRT40,WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.
| 本文言語 | English |
|---|---|
| ページ（範囲） | 511-529 |
| ページ数 | 19 |
| ジャーナル | Journal of the American Society of Nephrology |
| 巻 | 33 |
| 号 | 3 |
| DOI | |
| 出版ステータス | Published - 2022 3月 |
| 外部発表 | はい |
ASJC Scopus subject areas
- 腎臓病学
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Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin. / Joseph, Christina B.; Mariniello, Marta; Yoshifuji, Ayumi その他.
In: Journal of the American Society of Nephrology, Vol. 33, No. 3, 03.2022, p. 511-529.研究成果: Article › 査読
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TY - JOUR
T1 - Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin
AU - Joseph, Christina B.
AU - Mariniello, Marta
AU - Yoshifuji, Ayumi
AU - Schiano, Guglielmo
AU - Lake, Jennifer
AU - Marten, Jonathan
AU - Richmond, Anne
AU - Huffman, Jennifer E.
AU - Campbell, Archie
AU - Harris, Sarah E.
AU - Troyanov, Stephan
AU - Cocca, Massimiliano
AU - Robino, Antonietta
AU - Thériault, Sébastien
AU - Eckardt, Kai Uwe
AU - Wuttke, Matthias
AU - Cheng, Yurong
AU - Corre, Tanguy
AU - Kolcic, Ivana
AU - Black, Corrinda
AU - Bruat, Vanessa
AU - Concas, Maria Pina
AU - Sala, Cinzia
AU - Aeschbacher, Stefanie
AU - Schaefer, Franz
AU - Bergmann, Sven
AU - Campbell, Harry
AU - Olden, Matthias
AU - Polasek, Ozren
AU - Porteous, David J.
AU - Deary, Ian J.
AU - Madore, Francois
AU - Awadalla, Philip
AU - Girotto, Giorgia
AU - Ulivi, Sheila
AU - Conen, David
AU - Wuehl, Elke
AU - Olinger, Eric
AU - Wilson, James F.
AU - Bochud, Murielle
AU - Köttgen, Anna
AU - Hayward, Caroline
AU - Devuyst, Olivier
N1 - Funding Information: A. Ko€ttgen reports receiving honoraria from Sanofi Genzyme; reports being a scientific advisor or member of the American Kidney Fund, American Journal of Kidney Diseases, Journal of the American Society of Nephrology, Kidney International, and Nature Reviews Nephrology. C. Black reports having other interests/relationships through an honorary contract with the National Health Service. D. Conen reports consultancy agreements with Roche Diagnostics; reports receiving research funding from the Canadian Institutes of Health Research; and reports receiving honoraria from Bristol Myers Squibb/Pfizer. E. Wuehl reports being a scientific advisor to or member of the Alnylam Pharmaceuticals Advisory Board, Editorial Board Member of the Journal of Hypertension and Pediatric Nephrology, Executive Board Member of the German Hypertension League (Deutsche Hochdruckliga), and Vice-Chair COST Action Hyper-ChildNET (EU Programme Horizon 2020). F. Madore reports receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoS-mithKline, and Janssen; and reports being a scientific advisor or membership as Associate Editor for the Canadian Journal of Kidney Health and Disease. F. Schaefer reports having consultancy agreements with Akebia, Amgen, Alexion, Alnylam, Astellas, AstraZeneca, Bayer, Boehringer Ingel-heim, Fresenius Medical Care, Otsuka, Roche, and Relypsa; reports receiving research funding from Fresenius Medical Care; reports receiving honoraria from Amgen, Gilead, Otsuka, Relypsa, and Roche; and reports being a scientific advisor or member of the Scientific Advisory Board activities for Alexion and Otsuka. M. Bochud reports receiving research funding from Merck Sharp & Dohme; reports receiving honoraria from various Swiss Federal Agencies (Swiss Federal Office of Public Health, Swiss Federal Office of Food Security and Veterinary Affairs); reports being a scientific advisor or member of scientific journals, such as Nutrients and Hypertension, Member of the Council of the Swiss Society of Public Health Plus, Member of the Council of the The National Institute for Cancer Epidemiology and Registration (NICER) Foundation (cancer epidemiology in Switzerland), representative of the University of Lausanne at the Swiss Academy of Medical Sciences; and reports other interests/relationships as a member of the Swiss Federal Commission on Nutrition, the Swiss Society of Hypertension, the Swiss Society of Nephrology, the Swiss Society of Nutrition, the Swiss Society of Public Health Plus. O. Devuyst reports having consultancy agreements with Alnylam, Galapagos, Otsuka Pharmaceuticals, and Sanofi; reports receiving research funding from Otsuka Pharmaceuticals and Roche; reports being a scientific advisor or member of the editorial board of CJASN, Kidney International, Nephrology Dialysis Transplantation, Pflu€gers Archiv, Peritoneal Dialysis International, and Orphanet Journal of Rare Diseases. K. Eckardt reports consultancy agreements with Akebia, AstraZeneca, Bayer, Boehringer Ingelheim, Genzyme, Otsuka, Travere, and Vifor; research funding from Amgen, AstraZeneca, Bayer, Evotec, Fresenius, Genzyme, Shire, and Vifor; honoraria from Akebia, AstraZeneca, Bayer, Boehringer Ingelheim, Gen-zyme, Otsuka, Travere, and Vifor; and advisory or leadership role with KI and BMJ (editorial boards). All remaining authors have nothing to disclose. Funding Information: We are grateful for the willingness of the patients to participate in the study and CRediT Taxonomy. O. Devuyst and C. Hayward conceptualized the study; S. Aeschbacher, P. Awadalla, C. Black, S. Bergmann, M. Bochud, V. Bruat, A. Campbell, H. Campbell, M. Cocca, M. Concas, D. Conen, T. Corre, I. Deary, O. Devuyst, K.-U. Eckardt, G. Girotto, S. Harris, C. Hayward, J. Huffman, C. Joseph, I. Kolcic, A. Ko€ttgen, F. Madore, M. Mariniello, J. Marten, M. Olden, E. Olinger, O. Polasek, D. Porteous, A. Robino, F. Schaefer, G. Schiano, S. Thèriault, S. Troyanov, S. Ulivi, J. Wilson, E. Wu€hl, M. Wuttke, an A. Yoshifuji were responsible for the data curation; S. Aeschbacher, P. Awadalla, C. Black, S. Bergmann, M. Bochud, V. Bruat, M. Cocca, M. Concas, D. Conen, T. Corre, I. Deary, O. Devuyst, K.-U. Eckardt, G. Girotto, S. Harris, C. Hayward, J. Huffman, C. Joseph, A. Ko€ttgen, F. Madore, M. Mariniello, J. Marten, M. Olden, E. Olinger, A. Richmond, A. Robino, C. Sala, G. Schiano, S. Thèriault, S. Troyanov, S. Ulivi, J. Wilson, E. Wu€hl, M. Wuttke, and A. Yoshifuji were responsible for the formal analysis; H. Campbell, O. Devuyst, C. Hayward, and S. Troyanov were responsible for the funding acquisition; Y. Cheng, O. Devuyst, C. Hayward, C. Joseph, J. Lake, M. Mariniello, G. Schiano, S. Troyanov, and A. Yoshifuji were responsible for the investigation; T. Corre, O. Devuyst, C. Hayward, C. Joseph, J. Lake, M. Mariniello, J. Marten, M. Olden, G. Schiano, and A. Yoshifuji were responsible for the methodology; A. Campbell, H. Campbell, O. Devuyst, S. Harris, C. Hayward, and D. Porteous were responsible for the project administration; S. Aeschbacher, P. Awadalla, C. Black, S. Bergmann, M. Bochud, V. Bruat, A. Campbell, H. Campbell, Y. Cheng, M. Cocca, M. Concas, D. Conen, T. Corre, I. Deary, O. Devuyst, K.-U. Eckardt, G. Girotto, S. Harris, C. Hayward, J. Huffman, A. Ko€ttgen, F. Madore, M. Olden, E. Olin-ger, O. Polasek, D. Porteous, A. Robino, C. Sala, F. Schaefer, S. Thèriault, S. Troyanov, S. Ulivi, J. Wilson, E. Wu€hl, and M. Wuttke were responsible for the resources; O. Devuyst provided supervision; O. Devuyst, C. Hayward, S. Troyanov, and A. Yoshifuji were responsible for the validation; O. Devuyst, C. Hayward, C. Joseph, J. Lake, M. Mariniello, and G. Schiano were responsible for the visualization; O. Devuyst, C. Hayward, C. Joseph, and A. Yoshifuji wrote the original draft; S. Aeschbacher, P. Awadalla, C. Black, S. Bergmann, M. Bochud, V. Bruat, A. Campbell, H. Campbell, Y. Cheng, M. Cocca, M. Concas, D. Conen, T. Corre, I. Deary, O. Devuyst, K.-U. Eckardt, G. Girotto, I. Kolcic, A. Ko€ttgen, A. Robino, S. Harris, C. Hayward, J. Huffman, C. Joseph, J. Lake, F. Madore, M. Mariniello, J. Marten, M. Olden, E. Olinger, O. Polasek, D. Porteous, A. Richmond, C. Sala, F. Schaefer, G. Schiano, S. Thèriault, S. Troyanov, S. Ulivi, J. Wilson, E. Wu€hl, M. Wuttke, and A. Yoshifuji reviewed and edited the manuscript. We deeply acknowledge Professor John Starr (1960–2018), founding Director of the Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom, who contributed in the early phase of this study. The help of Larissa Gov-ers and Huguette Debaix (UZH, Zurich) is deeply appreciated. We thank Aleksander Edelman (Institut Necker Enfants Malades, Paris, France) for fruitful discussions on keratins. CARTaGENE: We thank the dedicated team at CARTaGENE for their diligent help. CoLaus: The computations for CoLaus imputation were performed in part at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics. M. Bochud is supported by the Swiss School of Public Health Plus. CROATIA-Korcula, CROATIA-Split, CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited, to the University of Split and Zagreb Medical Schools, Institute for Anthropological Research in Zagreb, and the Croatian Institute for Public Health. We also thank all of the participants from the islands of Vis and Korcula and the city of Split. FHS: This research was conducted in part using data and resources from the FHS of the National Institutes of Health National Heart Lung and Blood Institute (NHLBI) and Boston University School of Medicine. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. GCKD: Genotyping was supported by Bayer Pharma AG. The GCKD study was/is funded by grants from the Federal Ministry of Education and Research (BMBF, grant number 01ER0804) and the KfH Foundation for Preventive Medicine. We are grateful for the willingness of the patients to participate in the GCKD study. The enormous effort of the study personnel of the various regional centers is highly appreciated. We thank the many nephrologists who provide routine care for the patients and collaborate with the GCKD study. GS:SFHS: We are grateful to all of the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants, and nurses. GS:SFHS is supported by the Wellcome Trust (216767/Z/19/Z). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” Reference 104036/Z/14/Z). INGI-Carlantino and INGI-Val Borbera: We would like to thank the people of Carlantino and of the Val Borbera Valley for the everlasting support. LBC: The authors thank all LBC study participants and research team members who have contributed, and continue to contribute, to ongoing LBC studies. Genotyping was funded by the Biotechnology and Biological Sciences Research Council (BB/F019394/ 1). VIKING: We would like to acknowledge the invaluable contributions of the research nurses in Shetland, the administrative team in Edinburgh and the people of Shetland. We thank the UK Biobank Resource, approved under application 19655. The authors would like to thank the Rivas lab for making the Global Biobank Engine resource available. DNA extractions and genotyping were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke. The data used for the analyses described in this manuscript were obtained from the GTEx Portal (V8) on December 14, 2020. Funding Information: This work was supported by the Swiss National Science Foundation (project grant 310030_189044), the University Research Priority Program Innovative Therapies in Rare Diseases of the University of Zurich (UZH), the Swiss National Centre of Competence in Research, Kidney Control of Homeostasis (Kidney.CH), and the TrainCKDis project, funded by the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement 860977 (to O. Devuyst) and by an Medical Research Council University Unit Programme grant MC_UU_00007/10 (QTL in Health and Disease) (to C. Hayward). CARTaGENE is supported by the Kidney Foundation of Canada and the Fonds de la Recherche du Québec-Santé. CoLaus received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (33CSCO-122661, 3200BO-111361/2, 3100AO-116323/1, and 310000-112552). The CROATIA_Vis, CROATIA_Korcula, and CROATIA_Split studies were funded by European Commission Framework 6 project EUROSPAN (contract LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants (108-1080315-0302). The FHS is supported by the National Heart, Lung, and Blood Institute (FHS contract N01-HC-25195). The Genetic and Phenotypic Determinants of Blood Pressure and other Cardiovascular Risk Factors study was supported by the Liechtenstein Government, the Swiss Heart Foundation, the Swiss Society of Hypertension, the University Hospital Basel, the Hanela Foundation, the Mach-Gaensslen Foundation, Schiller AG, and Novartis. The GCKD study was supported by the German Ministry of Education and Research (Bundesministerium fu€r Bildung und Forschung, grants FKZ 01ER 0804, 01ER 0818, 01ER 0819, 01ER 0820 and 01ER 0821) and the KfH Foundation for Preventive Medicine (Kuratorium fu€r Heimdialyse und Nierentransplantation e.V.–Stiftung Pr€aventivmedizin) and corporate sponsors (www.gckd.org). The work of A. Kottgen and M. Wuttke is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) Project-ID 431984000– SFB 1453. GS:SFHS received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). INGI-Carlantino and INGI-Val Borbera were supported by Italian Ministry of Health grants RC 35/17 and D70-RESRICGIROTTO. The LBC1936 is supported by Age UK (Disconnected Mind project) and the Medical Research Council (MR/M01311/ 1, MR/K026992/1). The Viking Health Study– Shetland was supported by Medical Research Council University Unit Programme (MC_UU_00007/10, QTL in Health and Disease). Publisher Copyright: © 2022 by the American Society of Nephrology.
PY - 2022/3
Y1 - 2022/3
N2 - Background Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. Methods We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. Results Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. Conclusions Common variants in KRT40,WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.
AB - Background Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. Methods We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. Results Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. Conclusions Common variants in KRT40,WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.
UR - http://www.scopus.com/inward/record.url?scp=85125587432&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125587432&partnerID=8YFLogxK
U2 - 10.1681/ASN.2021040491
DO - 10.1681/ASN.2021040491
M3 - Article
C2 - 35228297
AN - SCOPUS:85125587432
SN - 1046-6673
VL - 33
SP - 511
EP - 529
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 3
ER -