Citations 2
A blueprint for pursuing therapeutic interventions and early phase clinical trials in clonal haematopoiesis
Haque, Tamanna , King, Zoe, Kishtagari, Ashwin , Madanat, Yazan F. , Borate, Uma , Slosky, David, Patnaik, Mrinal S., Bick, Alexander G., Verma, Amit , Jaiswal, Siddhartha , Kishtagari, Ashwin , Madanat, Yazan , Steensma, David P , Savona, Michael R , Jaiswal, Siddhartha , Shastri, Aditi , Desai, Pinkal , Xie, Zhuoer , Hammond, Danielle , Abaza, Yasmin , Silver, Alexander J. , Singh, Abhay , Heimlich, Jonathan Brett , Bolton, Kelly L. , Patnaik, Mrinal S., Bick, Alexander G. , Steensma, David P. , Savona, Michael R.
British Journal of Haematology | December 10, 2024 | Volume: 206 | Issue: 2 | Pages: 416-427
SummaryThe age‐associated mutational state of clonal haematopoiesis (CH) is linked to multiple adverse health outcomes. As higher risk CH can lead to progressive neoplastic or vascular disease, there is interest in developing clinical trials to mitigate risk associated with CH. Given the high prevalence of CH, data from clinical trials could have broad public health implications for screening and therapy. Thoughtful consideration is needed to design trials that are both clinically relevant and avoid overmedicalization. Here, we summarize clinical studies of CH to date and provide suggestions and guidance on how to approach designing CH‐focused therapeutic clinical trials. These recommendations are derived from discussions among clinical researchers and scientists emanating from the Inaugural Meeting on Somatic Mutations and Predisease in October 2021.
Genomic and phenomic landscape of clonal hematopoiesis in over a million ancestrally diverse participants
Uddin, Md Mesbah , Weinstock, Joshua S. , Niroula, Abhishek , Vlasschaert, Caitlyn , Koyama, Satoshi , Nakao, Tetsushi , Urbut, Sarah , Paruchuri, Kaavya , Silver, Alexander J. , Mack, Taralynn , Wong, Megan , Bhattacharya, Romit , Jorshery, Saman Doroodgar , Raddatz, Michael A. , Hornsby, Whitney , Kresge, Hailey A. , Cho, Kelly , Sun, Yan V. , Pyarajan, Saiju , Chen, Yii‐Der Ida , Sheu, Wayne H-H , Hung, Yi‐Jen , Hidalgo, Bertha , Fornage, Myriam , Kaplan, Robert C., Williams, L. Keoki , Province, Mike , Kardia, Sharon, Peyser, Patricia A., Yanek, Lisa R. , Becker, Lewis C. , Meyers, Deborah A. , Naseri, Take, Barnes, Kathleen C. , Redline, S S, Schwartz, D A, Shoemaker, M. Benjamin , Palmer, Nicholette D., Bowden, Donald W., Kumar, Rajesh, Nj, Smith, Floyd, James, Tracy, Russell, Bis, Joshua C. , SS, Rich, Boerwinkle, Eric, Wang, Zhe, Silverman, Edwin K. , Auer, Paul L. , Reiner, Alexander P. , Ebert, Benjamin L. , Natarajan, Pradeep , Uddin, Md M , Niroula, Abhishek , Weinstock, Joshua S , Bhattacharya, Romit , Ebert, Benjamin L , Natarajan, Pradeep , Yu, Zhi , Zekavat, Seyedeh M , Truong, Buu Minh Thanh , Haidermota, Sara , Honigberg, Michael C. , Zhang, Martin Jinye , Dron, Jacqueline S. , Heimlich, Jonathan Brett , Sankaran, Vijay G. , Griffin, Gabriel K. , Gibson, Christopher James , Wilson, Peter W.F. , Genovese, Giulio , Xu, Yaomin , Savona, Michael R. , Raffield, Laura M. , Arnett, Donna K. , Konkle, Barbara A. , Peyser, Patricia A. , Smith, Jennifer A. , Mathias, Rasika A. , Andrade, Mariza de , Darbar, Dawood , He, Jiang , Blangero, John , Weiss, Scott T. , Custer, Brian , Minster, Ryan L , Viali, Satupaitea , Mitchell, Braxton D. , Palmer, Nicholette D , Freedman, Barry I. , Bowden, Donald W. , Albert, Christine M. , Smith, Nicholas, Tracy, Russell P. , Psaty, Bruce M. , Taylor, Kent D. , Rotter, Jerome I. , Boerwinkle, Eric , Vasan, Ramachandran S. , Lubitz, Steven A. , Ellinor, Patrick T. , Loos, Ruth J. F. , Yun, Jeong H. , Cho, Michael H. , Abecasis, Gonçalo R. , Kooperberg, Charles , Reiner, Alex P. , Jaiswal, Siddhartha , Bick, Alexander G.
No container title available | July 31, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.