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. 2017 Jul 13;377(2):111-121.
doi: 10.1056/NEJMoa1701719. Epub 2017 Jun 21.

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

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Free PMC article

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

Siddhartha Jaiswal et al. N Engl J Med. .
Free PMC article

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.

Methods: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.

Results: In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.

Conclusions: The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).

Figures

Figure 1.
Figure 1.. CHIP associates with coronary heart disease
A) Forest plot for association between CHD and CHIP in BioImage and MDC. Hazard ratio for having CHD in those with mutations was obtained by a Cox proportional hazards model adjusted for age, sex, type 2 diabetes, total cholesterol, high-density lipoprotein cholesterol, smoking status, and hypertension. B) Forest plot for association between MI and CHIP in ATVB and PROMIS. Odds ratio was obtained by a logistic regression model adjusted for age, sex, type 2 diabetes, smoking status. CHIP (clonal hematopoiesis of indeterminate potential), CHD (coronary heart disease), HR (hazard ratio), MDC (Malmo Diet and Cancer Study), VAF (variant allele fraction), MI (myocardial infarction), OR (odds ratio), ATVB (Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group), PROMIS (The Pakistan Risk of Myocardial Infarction Study)
Figure 2.
Figure 2.. Mutations in DNMT3A, TET2, ASXL1, and JAK2 associate with coronary heart disease
A) Forest plot for risk of CHD in BioImage and MDC by mutated gene. Hazard ratio for listed mutations was obtained by a fixed-effects meta-analysis of Cox proportional hazards models adjusted for age, sex, type 2 diabetes, total cholesterol, high-density lipoprotein cholesterol, triglycerides, smoking status, and hypertension from BioImage, MDC, and JHS/FUSION/FHS. B) Table for risk of early-onset MI in ATVB and PROMIS (combined analysis) by mutated gene. Odds ratio for having MI in those with listed mutations was obtained by Fisher’s exact test, p-values not adjusted for multiple hypothesis testing. C) Proportion of total mutations by gene among MI cases in ATVB and PROMIS versus CHD cases in Biolmage and MDC. For all forest plots, black square represents the point estimate of hazard ratio, horizontal lines are the 95% confidence interval, vertical line signifies hazard ratio of 1, and results that were from a meta-analysis are shown as diamonds. CHIP (clonal hematopoiesis of indeterminate potential), Ml (myocardial infarction), Inf. (infinity), CHD (coronary heart disease), HR (hazard ratio), OR (odds ratio), ATVB (Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group), PROMIS (The Pakistan Risk of Myocardial Infarction Study), MDC (Malmo Diet and Cancer Study), FHS (Framingham Heart Study), JHS (Jackson Heart Study), FUSION (Finland United States Study of NIDDM Genetics)
Figure 3.
Figure 3.. CHIP associates with greater coronary artery calcification
A) Coronary artery calcification scores in those with or without CHIP, stratified by incident CHD. P-value obtained by a linear regression model adjusted for incident CHD status. Median score for each group is shown. B) Forest plot for association between coronary artery calcification score ≥615 and mutation status stratified by VAF in those without incident CHD in BioImage. Odds ratio was obtained by a logistic regression model adjusted for age, sex, type 2 diabetes, total cholesterol, high-density lipoprotein cholesterol, smoking status, and hypertension. CHIP (clonal hematopoiesis of indeterminate potential), CAC (coronary artery calcification), VAF (variant allele fraction), odds ratio (OR)
Figure 4.
Figure 4.. Loss of Tet2 in hematopoietic cells accelerates atherosclerosis in a mouse model
A) Aortic root sections in female Ldlr−/− mice transplanted with either Tet2+/+; Vav1-Cre (WT) or Tet2−/−; Vav1-Cre (KO) marrow after 5 and 9 weeks of feeding on high cholesterol diet. Oil red O (left) and Masson’s trichrome (right) images are shown (40X magnification). Dashed lines indicate lesion area. B) Quantification of aortic root lesions in female Ldlr−/− mice transplanted with either Tet2+/+; Vav1-Cre (WT), Tet2+/−; Vav1-Cre (HET), or Tet2−/−; Vav1-Cre (KO) marrow at 5 and 9 weeks on diet. P-values obtained by Wilcoxon rank-sum test. C) Descending aorta lesions stained with oil red O at 17 weeks in female Ldlr−/− mice transplanted with either Tet2+/+; Vav1-Cre (WT), Tet2+/−; Vav1-Cre (HET), or Tet2−/−; Vav1-Cre (KO) marrow. D) Quantification of descending aorta lesions at 17 weeks in female Ldlr−/− mice transplanted with either Tet2+/+; Vav1-Cre (WT), Tet2+/−; Vav1-Cre (HET), or Tet2−/−; Vav1-Cre (KO) marrow. P-values obtained by Dunn’s Kruskal-Wallis test for multiple comparisons using Benjamini-Hochberg correction.black horizontal line represents the median value.

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