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Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease

Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease
Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease

We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10 –4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10 –8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = −3.36, P = 0.01) and somatic driver mutations (n = 3241, β = −1.08, P = 6.25 × 10 –5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.

0887-6924
507-515
Dawoud, Ahmed, Abdelrazek Zaky
23beaa7f-ab38-4ac3-9624-f37ab9110c2c
Gilbert, Rodney
c69c5b99-2a15-4502-acd8-36b254d42601
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Cross, Nicholas
f87650da-b908-4a34-b31b-d62c5f186fe4
Dawoud, Ahmed, Abdelrazek Zaky
23beaa7f-ab38-4ac3-9624-f37ab9110c2c
Gilbert, Rodney
c69c5b99-2a15-4502-acd8-36b254d42601
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Cross, Nicholas
f87650da-b908-4a34-b31b-d62c5f186fe4

Dawoud, Ahmed, Abdelrazek Zaky, Gilbert, Rodney, Tapper, William and Cross, Nicholas (2022) Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease. Leukemia, 36 (2), 507-515. (doi:10.1038/s41375-021-01382-3).

Record type: Article

Abstract

We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10 –4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10 –8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = −3.36, P = 0.01) and somatic driver mutations (n = 3241, β = −1.08, P = 6.25 × 10 –5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.

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Accepted/In Press date: 2 August 2021
Published date: 1 February 2022
Additional Information: Funding Information: AAZD was supported by a Lady Tata International Award; NCPC and WJT were supported by Blood Cancer UK. The authors acknowledge the use of the IRIDIS High Performance Computing Facility and associated support services at the University of Southampton. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2022 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 450711
URI: http://eprints.soton.ac.uk/id/eprint/450711
ISSN: 0887-6924
PURE UUID: 5fc3b485-f52e-46d7-86bf-3de59d07abf6
ORCID for Ahmed, Abdelrazek Zaky Dawoud: ORCID iD orcid.org/0000-0003-0164-7773
ORCID for Rodney Gilbert: ORCID iD orcid.org/0000-0001-7426-0188
ORCID for William Tapper: ORCID iD orcid.org/0000-0002-5896-1889
ORCID for Nicholas Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 09 Aug 2021 16:30
Last modified: 13 Jan 2023 02:56

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Contributors

Author: Ahmed, Abdelrazek Zaky Dawoud ORCID iD
Author: Rodney Gilbert ORCID iD
Author: William Tapper ORCID iD
Author: Nicholas Cross ORCID iD

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