Nat Commun. 2021;12(1):5975.

Clonal hematopoiesis is associated with risk of severe Covid-19.

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

제1저자 Kelly L Bolton, 고영일, Michael B Foote, 임호균, Justin Jee, 선충현, Anton Safonov, 김의석, 김남중, Ahmet Zehir. · 교신저자 Kelly L Bolton, 김의석, 김남중, Ahmet Zehir.

PMID 34645798 PMC8514469 DOI 10.1038/s41467-021-26138-6 IF 18.1 감염내과

소속 (24)

Department of Medicine, Washington University, St Louis, MO, USA. bolton@wustl.edu.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Genome Opinion Inc., Seoul, Korea.
Center for Precision Medicine, Seoul National University Hospital, Seoul, Korea.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea.
Department of Internal Medicine, National Medical Center, Seoul, Korea.
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Washington University, St Louis, MO, USA.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Computational Oncology Service, Department of Epidemiology & Biostatistics, Center for Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Ontario Institute for Cancer Research, Toronto, ON, Canada.
Clinical Genetics Research Lab, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea. eskim@snubh.org.
Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. molder@unitel.co.kr.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. zehira@mskcc.org.

Abstract

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10^-3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10^-3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

Figures

**Fig. 1** Association between CH and Covid-19 severity. Shown are the results from logistic regression adjusted for age, gender, race, smoking, diabetes, cardiovascular disease, COPD/asthma, BMI, and month of Covid-19 diagnosis in 525 individuals. The MSK cohort was also adjusted for cancer primary site, exposure to cytotoxic cancer therapy before and after blood draw. Summary statistics for a fixed-effects meta-analysis are shown. Any CH includes both driver (CH-PD) and non-driver mutations (CH-non-PD).

**Fig. 2** Association between CH and risk of infection in 14,211 solid tumor patients. A Volcano plot of the log(Hazard ratio) of infection with CH using multivariable cox proportional hazards regression. Any CH includes both driver (CH-PD) and non-driver mutations (CH-non-PD). B Association between CH subtype defined by CH putative driver status and risk of *Clostridium Difficle* (N = 189) and *Streptococcus/Enterococcus* (N = 501) infection using cox proportional hazards regression. All models were adjusted for age, gender, race, smoking, cancer primary site, cumulative exposure to cytotoxic cancer therapy before and after blood draw. Shown is the hazard ratio for infection, associated 95% confidence interval, and p value (not adjusted or multiple comparisons).

그림 출처: PubMed Central 공개 논문 (PMC8514469)

Comment · 정정

Update of medRxiv. 2020 Nov 27:2020.11.25.20233163. doi: 10.1101/2020.11.25.20233163.

Conflict of interest statement

The authors declare the following competing interests: K.B. has received research funding from GRAIL and Bristol Myers Squibb; Y.K. is a co-founder in Genome Opinion. M.F.B. is on the advisory board for Roche and receives research support from Illumina. J.J. has a patent licensed by the company MDSeq Inc. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Loxo, Imago, C4 Therapeutics, and Isoplexis, which include equity interest. He receives research support from and consulted for Celgene and Roche and has consulted for Lilly, Janssen, Astellas, Morphosys, and Novartis. He has received honoraria from Roche, Lilly, and Amgen for invited lectures and from Gilead for grant reviews. A.Z. received honoraria from Illumina. E.P. receives research funding from Celgene. D.G. and has received honoraria for speaking and scientific advisory engagements with Celgene, Prime Oncology, Novartis, Illumina, and Kyowa Hakko Kirin and is a co-founder in Isabl Technologies. M. Ladanyi has served on the advisory boards for AstraZeneca, Bristol Myers Squibb, Takeda, Bayer, BluePrint, Pfizer, Janssen, and Merck, and has received research support from Loxo Oncology and Helsinn Therapeutics, and Elevation Oncology. L.A.D. is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics; is a paid consultant to PGDx and Neophore; is an uncompensated consultant for Merck (with the exception of travel and research support for clinical trials); is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University, some of which are associated with equity or royalty payments directly to Johns Hopkins and L.A.D.; and holds equity in PGDx, Jounce Therapeutics, Thrive Earlier Detection and Neophore; his wife holds equity in Amgen. The terms of all of these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. H.I., C.H.S., H.S., S.K. are current employees of Genome Opinion and holds stock in the company. All other authors declare no competing interests.

그 밖의 정보