title: Age-related clonal hematopoiesis associated with adverse outcomes.
abstract: BACKGROUND
  The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.
  
  
  METHODS
  We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events.
  
  
  RESULTS
  Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8).
  
  
  CONCLUSIONS
  Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Jaiswal
authors.forename: Pierre
authors.initials: P
authors.lastname: Fontanillas
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.forename: Alisa
authors.initials: A
authors.lastname: Manning
authors.forename: Peter V
authors.initials: PV
authors.lastname: Grauman
authors.forename: Brenton G
authors.initials: BG
authors.lastname: Mar
authors.forename: R Coleman
authors.initials: RC
authors.lastname: Lindsley
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mermel
authors.forename: Noel
authors.initials: N
authors.lastname: Burtt
authors.forename: Alejandro
authors.initials: A
authors.lastname: Chavez
authors.forename: John M
authors.initials: JM
authors.lastname: Higgins
authors.forename: Vladislav
authors.initials: V
authors.lastname: Moltchanov
authors.forename: Frank C
authors.initials: FC
authors.lastname: Kuo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kluk
authors.forename: Brian
authors.initials: B
authors.lastname: Henderson
authors.forename: Leena
authors.initials: L
authors.lastname: Kinnunen
authors.forename: Heikki A
authors.initials: HA
authors.lastname: Koistinen
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Adolfo
authors.initials: A
authors.lastname: Correa
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Banahan
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.forename: Heather M
authors.initials: HM
authors.lastname: Stringham
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Christopher
authors.initials: C
authors.lastname: Haiman
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001769:Blood; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002999:Clone Cells; D004252:DNA Mutational Analysis; D059472:Exome; D019337:Hematologic Neoplasms / Q000235:genetics*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D055815:Young Adult