Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank
Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the aging-related clonal expansion of preleukemic mutations in hematopoietic stem cells. While CHIP has been studied in cardiometabolic diseases (CMDs), its role in the long-term progression from the absence of...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | European Journal of Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40001-025-02639-8 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850125567468240896 |
|---|---|
| author | Chenzhe Zuo Dihan Fu Yuanfeng Huang Jinchen Li Shujun Yang Xunjie Cheng Guogang Zhang Tianqi Ma Qunyong Peng Yu Tan |
| author_facet | Chenzhe Zuo Dihan Fu Yuanfeng Huang Jinchen Li Shujun Yang Xunjie Cheng Guogang Zhang Tianqi Ma Qunyong Peng Yu Tan |
| author_sort | Chenzhe Zuo |
| collection | DOAJ |
| description | Abstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the aging-related clonal expansion of preleukemic mutations in hematopoietic stem cells. While CHIP has been studied in cardiometabolic diseases (CMDs), its role in the long-term progression from the absence of CMD to the development of a single CMD, cardiometabolic multimorbidity (CMM), and eventual mortality remains uncertain. This study aimed to investigate the association between CHIP and gene-specific CHIP subtypes with the progression of CMD transitions. Methods We included UK Biobank participants without CMD at baseline. The primary outcomes were the first CMD, CMM, and death. We evaluated associations between any CHIP (variant allele fraction [VAF] ≥ 2%), large CHIP (VAF ≥ 10%), and gene-specific CHIP subtypes (DNMT3 A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage genes], and SF3B1/SRSF2/U2 AF1 [spliceosome genes]) with CMD transitions via multistate model analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with age as the time scale, and adjusted for sex, race, Townsend Deprivation Index, body mass index (BMI), smoking, alcohol, physical activity, sleep duration, and hypertension. Results The study included 371,544 participants, with a mean age of 56.60 (± 8.03) years, and 44.2% of whom were male (CHIP: n = 11,570 [3.1%]; large CHIP: n = 7156 [1.9%]). During a median follow-up period of 14.49 years, 54,805 individuals developed at least one CMD, 8090 experienced CMM, and 26,218 died. In the fully adjusted multistate models, CHIP and large CHIP were associated with adjusted hazard ratios (HR) of 1.11 (95% CI 1.07–1.16) and 1.14 (95% CI 1.08–1.20), respectively, for transitioning from a CMD-free condition to a single CMD. The mortality risk associations were strongest, with adjusted HR of 1.45 (95% CI 1.36–1.55) and 1.64 (95% CI 1.52–1.77) for those without CMD, 1.39 (95% CI 1.26–1.54) and 1.59 (95% CI 1.41–1.79) for individuals with single CMD, and 1.58 (95% CI 1.31–1.91) and 1.61 (95% CI 1.29–2.02) for those with CMM. No significant association was observed with CMM development. Gene-specific analyses identified DNMT3 A, TET2, DNA damage genes, and spliceosome genes as the primary contributors to increased CMD risk. While CHIP showed no association with CMM progression, spliceosome genes were linked to a 1.72-fold higher risk (adjusted HR 1.72, 95% CI 1.14–2.59) of recurrent CMD events. All CHIP subtypes were strongly related to a heightened risk of mortality, with JAK2 presenting the highest adjusted odds ratio at 6.79 (95% CI 4.12–11.2). Conclusions CHIP serves as an independent risk factor for transitioning to the first CMD incidence and for mortality but is not associated with CMM development. CHIP-targeted management may represent a promising strategy for the primary prevention of CMD and for reducing mortality risk. |
| format | Article |
| id | doaj-art-b8fd253478c24097bb48a9c5b0ec17da |
| institution | OA Journals |
| issn | 2047-783X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj-art-b8fd253478c24097bb48a9c5b0ec17da2025-08-20T02:34:06ZengBMCEuropean Journal of Medical Research2047-783X2025-05-0130111410.1186/s40001-025-02639-8Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK BiobankChenzhe Zuo0Dihan Fu1Yuanfeng Huang2Jinchen Li3Shujun Yang4Xunjie Cheng5Guogang Zhang6Tianqi Ma7Qunyong Peng8Yu Tan9Department of Cardiovascular Medicine, the Third Xiangya Hospital, Central South UniversityCenter of Coronary Circulation, Xiangya Hospital, Central South UniversityDepartment of Geriatrics, Xiangya Hospital and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, National Clinical Research Center for Geriatric Disorders, Central South UniversityDepartment of Geriatrics, Xiangya Hospital and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, National Clinical Research Center for Geriatric Disorders, Central South UniversityCenter of Coronary Circulation, Xiangya Hospital, Central South UniversityCenter of Coronary Circulation, Xiangya Hospital, Central South UniversityDepartment of Cardiovascular Medicine, the Third Xiangya Hospital, Central South UniversityCenter of Coronary Circulation, Xiangya Hospital, Central South UniversityCenter of Coronary Circulation, Xiangya Hospital, Central South UniversityCenter of Coronary Circulation, Xiangya Hospital, Central South UniversityAbstract Background Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the aging-related clonal expansion of preleukemic mutations in hematopoietic stem cells. While CHIP has been studied in cardiometabolic diseases (CMDs), its role in the long-term progression from the absence of CMD to the development of a single CMD, cardiometabolic multimorbidity (CMM), and eventual mortality remains uncertain. This study aimed to investigate the association between CHIP and gene-specific CHIP subtypes with the progression of CMD transitions. Methods We included UK Biobank participants without CMD at baseline. The primary outcomes were the first CMD, CMM, and death. We evaluated associations between any CHIP (variant allele fraction [VAF] ≥ 2%), large CHIP (VAF ≥ 10%), and gene-specific CHIP subtypes (DNMT3 A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage genes], and SF3B1/SRSF2/U2 AF1 [spliceosome genes]) with CMD transitions via multistate model analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with age as the time scale, and adjusted for sex, race, Townsend Deprivation Index, body mass index (BMI), smoking, alcohol, physical activity, sleep duration, and hypertension. Results The study included 371,544 participants, with a mean age of 56.60 (± 8.03) years, and 44.2% of whom were male (CHIP: n = 11,570 [3.1%]; large CHIP: n = 7156 [1.9%]). During a median follow-up period of 14.49 years, 54,805 individuals developed at least one CMD, 8090 experienced CMM, and 26,218 died. In the fully adjusted multistate models, CHIP and large CHIP were associated with adjusted hazard ratios (HR) of 1.11 (95% CI 1.07–1.16) and 1.14 (95% CI 1.08–1.20), respectively, for transitioning from a CMD-free condition to a single CMD. The mortality risk associations were strongest, with adjusted HR of 1.45 (95% CI 1.36–1.55) and 1.64 (95% CI 1.52–1.77) for those without CMD, 1.39 (95% CI 1.26–1.54) and 1.59 (95% CI 1.41–1.79) for individuals with single CMD, and 1.58 (95% CI 1.31–1.91) and 1.61 (95% CI 1.29–2.02) for those with CMM. No significant association was observed with CMM development. Gene-specific analyses identified DNMT3 A, TET2, DNA damage genes, and spliceosome genes as the primary contributors to increased CMD risk. While CHIP showed no association with CMM progression, spliceosome genes were linked to a 1.72-fold higher risk (adjusted HR 1.72, 95% CI 1.14–2.59) of recurrent CMD events. All CHIP subtypes were strongly related to a heightened risk of mortality, with JAK2 presenting the highest adjusted odds ratio at 6.79 (95% CI 4.12–11.2). Conclusions CHIP serves as an independent risk factor for transitioning to the first CMD incidence and for mortality but is not associated with CMM development. CHIP-targeted management may represent a promising strategy for the primary prevention of CMD and for reducing mortality risk.https://doi.org/10.1186/s40001-025-02639-8Cardiometabolic diseasesClonal hematopoiesisMultistate modelUK Biobank |
| spellingShingle | Chenzhe Zuo Dihan Fu Yuanfeng Huang Jinchen Li Shujun Yang Xunjie Cheng Guogang Zhang Tianqi Ma Qunyong Peng Yu Tan Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank European Journal of Medical Research Cardiometabolic diseases Clonal hematopoiesis Multistate model UK Biobank |
| title | Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank |
| title_full | Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank |
| title_fullStr | Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank |
| title_full_unstemmed | Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank |
| title_short | Association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality: a prospective study of UK Biobank |
| title_sort | association of clonal hematopoiesis of indeterminate potential with cardiometabolic multimorbidity progression and mortality a prospective study of uk biobank |
| topic | Cardiometabolic diseases Clonal hematopoiesis Multistate model UK Biobank |
| url | https://doi.org/10.1186/s40001-025-02639-8 |
| work_keys_str_mv | AT chenzhezuo associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT dihanfu associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT yuanfenghuang associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT jinchenli associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT shujunyang associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT xunjiecheng associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT guogangzhang associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT tianqima associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT qunyongpeng associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank AT yutan associationofclonalhematopoiesisofindeterminatepotentialwithcardiometabolicmultimorbidityprogressionandmortalityaprospectivestudyofukbiobank |