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.
507-515
Dawoud, Ahmed A Z.
01e458e9-68ea-45c1-9e8b-ef85e9ccc35e
Gilbert, Rodney D.
c69c5b99-2a15-4502-acd8-36b254d42601
Tapper, William J.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Cross, Nicholas C. P.
f87650da-b908-4a34-b31b-d62c5f186fe4
1 February 2022
Dawoud, Ahmed A Z.
01e458e9-68ea-45c1-9e8b-ef85e9ccc35e
Gilbert, Rodney D.
c69c5b99-2a15-4502-acd8-36b254d42601
Tapper, William J.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Cross, Nicholas C. P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Dawoud, Ahmed A Z., Gilbert, Rodney D., Tapper, William J. and Cross, Nicholas C. P.
(2022)
Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease.
Leukemia, 36 (2), .
(doi:10.1038/s41375-021-01382-3).
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.
Text
Dawoud Leukemia 2021
- Accepted Manuscript
Text
s41375-021-01382-3
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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.
Identifiers
Local EPrints ID: 450711
URI: http://eprints.soton.ac.uk/id/eprint/450711
ISSN: 0887-6924
PURE UUID: 5fc3b485-f52e-46d7-86bf-3de59d07abf6
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Date deposited: 09 Aug 2021 16:30
Last modified: 06 Nov 2024 05:01
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Author:
Ahmed A Z. Dawoud
Author:
Rodney D. Gilbert
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