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Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation.
Tuesday,2024-09-17 12:41 America/Los_Angeles — ecterry
| Title | Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Levy, D, Kirmani, S, Huan, T, Van Amburg, J, Joehanes, R, Uddin, MMesbah, Nguyen, NQuynh, Yu, B, Brody, J, Fornage, M, Bressler, J, Sotoodehnia, N, Ong, D, Puddu, F, Floyd, J, Ballantyne, C, Psaty, B, Raffield, L, Natarajan, P, Conneely, K, Carson, A, Lange, L, Ferrier, K, Heard-Costa, N, Murabito, J, Bick, A |
| Journal | Res Sq |
| Date Published | 2024 Jul 16 |
| ISSN | 2693-5015 |
| Abstract | <p>With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed "clonal hematopoiesis of indeterminate potential" (CHIP). How these mutations confer a proliferative advantage and result in increased risk for numerous age-related diseases remains poorly understood. We conducted a multiracial meta-analysis of epigenome-wide association studies (EWAS) of CHIP and its subtypes in four cohorts (N=8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. The EWAS findings were functionally validated using human hematopoietic stem cell (HSC) models of CHIP. A total of 9615 CpGs were associated with any CHIP, 5990 with DNMT3A CHIP, 5633 with TET2 CHIP, and 6078 with ASXL1 CHIP (P <1×10). CpGs associated with CHIP subtypes overlapped moderately, and the genome-wide DNA methylation directions of effect were opposite for TET2 and DNMT3A CHIP, consistent with their opposing effects on global DNA methylation. There was high directional concordance between the CpGs shared from the meta-EWAS and human edited CHIP HSCs. Expression quantitative trait methylation analysis further identified transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses revealed 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value <0.05). Taken together, our study sheds light on the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes. The novel genes and pathways linked to the epigenetic features of CHIP may serve as therapeutic targets for preventing or treating CHIP-mediated diseases.</p> |
| DOI | 10.21203/rs.3.rs-4656898/v1 |
| Alternate Journal | Res Sq |
| PubMed ID | 39070619 |
| PubMed Central ID | PMC11276001 |
| Grant List | HHSN268201100037C / HL / NHLBI NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States HHSN268201800012C / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States U01 HL120393 / HL / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States HHSN268201700002C / HL / NHLBI NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States HHSN268201800011C / HL / NHLBI NIH HHS / United States HHSN268201700004C / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States T32 GM080178 / GM / NIGMS NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States HHSN268201500001C / HL / NHLBI NIH HHS / United States HHSN268201800014I / HB / NHLBI NIH HHS / United States HHSN268201800014C / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States R01 HL168894 / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States HHSN268201700001I / HL / NHLBI NIH HHS / United States HHSN268201800013I / MD / NIMHD NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States HHSN268201800012I / HL / NHLBI NIH HHS / United States 75N92021D00006 / HL / NHLBI NIH HHS / United States HHSN268201700005C / HL / NHLBI NIH HHS / United States HHSN268201700001C / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States HHSN268201700003C / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States HHSN268201800015I / HB / NHLBI NIH HHS / United States HHSN268201700002I / HL / NHLBI NIH HHS / United States HHSN268201800010I / HB / NHLBI NIH HHS / United States HHSN268201700005I / HL / NHLBI NIH HHS / United States R01 HL117626 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States HHSN268201800011I / HB / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States HHSN268201700003I / HL / NHLBI NIH HHS / United States R01 HL148050 / HL / NHLBI NIH HHS / United States |
ePub date:
24/07