Zekavat, S.M., Lin, SH., Bick, A.G. et al. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nat Med 27, 1012–1024 (2021). https://doi.org/10.1038/s41591-021-01371-0
Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection
|Author:||Zekavat, Seyedeh M.1,2,3; Lin, Shu-Hong4; Bick, Alexander G.2,5;|
1Yale Univ, Computat Biol & Bioinformat Program, New Haven, CT USA.
2Broad Inst Harvard & MIT, Med & Populat Genet & Cardiovasc Dis Initiat, Cambridge, MA 02142 USA.
3Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
4NCI, Integrat Tumor Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA.
5Vanderbilt Univ, Med Ctr, Dept Med, Div Genet Med, Nashville, TN USA.
6Inst Mol Med Finland, Helsinki, Finland.
7Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA.
8Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA.
9Columbia Univ, Vagelos Coll Phys & Surg, Dept Med, Div Nephrol, New York, NY USA.
10RIKEN, Ctr Integrat Med Sci, Lab Stat & Translat Genet, Yokohama, Kanagawa, Japan.
11Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA.
12Harvard Med Sch, Boston, MA 02115 USA.
13Vertex Pharmaceut, Boston, MA USA.
14Broad Inst Harvard & MIT, Stanley Ctr, Cambridge, MA USA.
15Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.
16Columbia Univ, Irving Inst Clin & Translat Res, New York, NY USA.
17Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
18NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA.
19Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
20Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA.
21Brigham & Womens Hosp, Div Rheumatol Inflammat & Immun, 75 Francis St, Boston, MA 02115 USA.
22Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA.
23Partners Healthcare, Lab Mol Med, Cambridge, MA USA.
24Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
25Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka, Japan.
26Univ Shizuoka, Sch Pharmaceut Sci, Dept Appl Genet, Shizuoka, Japan.
27Yale Sch Publ Hlth, Dept Biostat, New Haven, CT USA.
28Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.
29Howard Hughes Med Inst, Boston, MA 02115 USA.
30Columbia Univ, Vagelos Coll Phys & Surg, Dept Med, Div Cardiol, New York, NY USA.
|Online Access:||PDF Full Text (PDF, 4.7 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022081855797
|Publish Date:|| 2021-12-07
Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age–related mosaic chromosomal alterations (mCAs) detected from genotyping of blood–derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15–1.36; P = 1.8 x 10-7), including sepsis (HR 2.68; 95% CI = 2.25–3.19; P = 3.1 x 10-28), pneumonia (HR 1.76; 95% CI = 1.53–2.03; P = 2.3 x 10-15), digestive system infections (HR 1.51; 95% CI = 1.32–1.73; P = 2.2 x 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11–1.41; P = 3.7 x 10-4). A genome–wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
|Pages:||1012 - 1024|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
P.N. is supported by a Hassenfeld Scholar Award from the Massachusetts General Hospital, and grants from the National Heart, Lung, and Blood Institute (R01HL1427, R01HL148565, and R01HL148050). P.N. and B.L.E. are supported by a grant from Fondation Leducq (TNE-18CVD04). S.M.Z is supported by the NIH National Heart, Lung, and Blood Institute (1F30HL149180-01) and the NIH Medical Scientist Training Program Training Grant (T32GM136651). A.G.B. is supported by a Burroughs Wellcome Fund Career Award for Medical Scientists. G.G is supported by NIH grant R01 HG006855, NIH grant R01 MH104964, and the Stanley Center for Psychiatric Research. J.P.P is supported by a John S LaDue Memorial Fellowship. K.P. is supported by NIH grant 5-T32HL007208-43. P.T.E. is supported by supported grants from the National Institutes of Health (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082), and by the Foundation Leducq (14CVD01). P.-R.L. is supported by NIH grant DP2 ES030554 and a Burroughs Wellcome Fund Career Award at the Scientific Interfaces. This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, extramural grants from the National Heart, Lung, and Blood Institute, and Fondation Leducq. The opinions expressed by the authors are their own and this material should not be interpreted as representing the official viewpoint of the U.S. Department of Health and Human Services, the National Institutes of Health, or the National Cancer Institute. The Columbia University Biobank is supported by the Vagelos College of Physicians & Surgeons as well as the Precision Medicine Resource and Biomedical Informatics Resource of Irving Institute for Clinical and Translational Research, home of the Columbia University’s Clinical and Translational Science Award (CTSA), funded by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873.
This is a post-peer-review, pre-copyedit version of an article published in Nature Medicine. The final authenticated version is available online at: http://dx.doi.org/10.1038/s41591-021-01371-0.