Figure 1.
Frequent blood donors show expected CH incidence but distinct DNMT3A mutation profile. (A) Characteristics of the FDs and CDs whose samples were collected and analyzed as 2 separate cohorts (cohort 1 and 2). (B) Percentage of donors with somatic mutations (hits) within the FD and CD cohorts. The cutoff for the VAF (clone size) was set to 0.005 (0.5%). Analysis with a conventional 0.02 (2%) cutoff is shown for comparison. Percentage values are indicated on the bars. Data from cohort 1 and 2 are plotted separately. For VAF cutoff 0.005: cohort 1 (adjusted odds ratio [OR], 1.81; confidence interval [CI], 0.95-3.49; P = .074) and cohort 2 (adjusted OR, 0.81; CI, 0.44-1.48; P = .49). For VAF cutoff 0.02: cohort 1 (adjusted OR, 1.33; CI, 0.58-3.09; P = .501) and cohort 2 (adjusted OR, 0.72; CI, 0.29-1.75; P = .47). (C) Lollipop plot charts with type and location of the mutations in DNMT3A shown (detected at a VAF ≥0.005). The events are color-coded based on their predicted effects on the protein (see legend). See supplemental Tables 2A-B and 3A-B for full lists of events. The locations of the PWWP, the ADD-type zinc finger, and the methyltransferase (MTase) domains are shown. Three exonic splice region DNMT3A mutations (c.2320 G>A, c.2477 A>G in the CD; and c.2477 A>G in the FD) are not depicted in the lollipop plot. Mutations from the (extended, see “Methods” for details) cohort 1 and cohort 2 are plotted together. Fisher test for independence between donor group and mutation class (P = .404). (D) Analysis of stability scores for DNMT3A mutations from the FD and CD cohorts that were matched to the variants characterized by Huang et al26 (see supplemental Table 3A-B; P < .001). Data from cohort 1 and 2 were combined. (E) Analysis of the fitness score (s value; growth per year) for DNMT3A mutations from the FD and CD cohort that were matched to the variants characterized by Watson et al27 (see supplemental Tables 3A-B and 5; P < .001). Data from cohort 1 and 2 are plotted together. ADD, ATRX, DNMT3, and DNMT3L; MTase, methyltransferase; n.s., non-significant; PWWP, proline-tryptophan-tryptophan-proline motif.

Frequent blood donors show expected CH incidence but distinct DNMT3A mutation profile. (A) Characteristics of the FDs and CDs whose samples were collected and analyzed as 2 separate cohorts (cohort 1 and 2). (B) Percentage of donors with somatic mutations (hits) within the FD and CD cohorts. The cutoff for the VAF (clone size) was set to 0.005 (0.5%). Analysis with a conventional 0.02 (2%) cutoff is shown for comparison. Percentage values are indicated on the bars. Data from cohort 1 and 2 are plotted separately. For VAF cutoff 0.005: cohort 1 (adjusted odds ratio [OR], 1.81; confidence interval [CI], 0.95-3.49; P = .074) and cohort 2 (adjusted OR, 0.81; CI, 0.44-1.48; P = .49). For VAF cutoff 0.02: cohort 1 (adjusted OR, 1.33; CI, 0.58-3.09; P = .501) and cohort 2 (adjusted OR, 0.72; CI, 0.29-1.75; P = .47). (C) Lollipop plot charts with type and location of the mutations in DNMT3A shown (detected at a VAF ≥0.005). The events are color-coded based on their predicted effects on the protein (see legend). See supplemental Tables 2A-B and 3A-B for full lists of events. The locations of the PWWP, the ADD-type zinc finger, and the methyltransferase (MTase) domains are shown. Three exonic splice region DNMT3A mutations (c.2320 G>A, c.2477 A>G in the CD; and c.2477 A>G in the FD) are not depicted in the lollipop plot. Mutations from the (extended, see “Methods” for details) cohort 1 and cohort 2 are plotted together. Fisher test for independence between donor group and mutation class (P = .404). (D) Analysis of stability scores for DNMT3A mutations from the FD and CD cohorts that were matched to the variants characterized by Huang et al26 (see supplemental Table 3A-B; P < .001). Data from cohort 1 and 2 were combined. (E) Analysis of the fitness score (s value; growth per year) for DNMT3A mutations from the FD and CD cohort that were matched to the variants characterized by Watson et al27 (see supplemental Tables 3A-B and 5; P < .001). Data from cohort 1 and 2 are plotted together. ADD, ATRX, DNMT3, and DNMT3L; MTase, methyltransferase; n.s., non-significant; PWWP, proline-tryptophan-tryptophan-proline motif.

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