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Common and rare variant associations with clonal haematopoiesis phenotypes.

ABSTRACT: Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes^1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes⁶, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

SUBMITTER: Kessler MD

PROVIDER: S-EPMC9713173 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Common and rare variant associations with clonal haematopoiesis phenotypes.

Kessler Michael D MD Damask Amy A O'Keeffe Sean S Banerjee Nilanjana N Li Dadong D Watanabe Kyoko K Marketta Anthony A Van Meter Michael M Semrau Stefan S Horowitz Julie J Tang Jing J Kosmicki Jack A JA Rajagopal Veera M VM Zou Yuxin Y Houvras Yariv Y Ghosh Arkopravo A Gillies Christopher C Mbatchou Joelle J White Ryan R RR Verweij Niek N Bovijn Jonas J Parikshak Neelroop N NN LeBlanc Michelle G MG Jones Marcus M Glass David J DJ Lotta Luca A LA Cantor Michael N MN Atwal Gurinder S GS Locke Adam E AE Ferreira Manuel A R MAR Deering Raquel R Paulding Charles C Shuldiner Alan R AR Thurston Gavin G Ferrando Adolfo A AA Salerno Will W Reid Jeffrey G JG Overton John D JD Marchini Jonathan J Kang Hyun M HM Baras Aris A Abecasis Gonçalo R GR Jorgenson Eric E

Nature 20221130 7939

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes<sup>1-5</sup>. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the ...[more]

PMID: 36450978

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Project description:AimsSomatic mutations in haematopoietic stem cells can lead to the clonal expansion of mutated blood cells, known as clonal haematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF) ≥ 2% have been associated with atherosclerosis and chronic heart failure of ischemic origin (CHF). However, the effects of mutations in other driver genes for CH with low VAF (<2%) on CHF are still unknown.Methods and resultsTherefore, we analysed mononuclear bone marrow and blood cells from 399 CHF patients by deep error-corrected targeted sequencing of 56 genes and associated mutations with the long-term mortality in these patients (3.95 years median follow-up). We detected 1113 mutations with a VAF ≥ 0.5% in 347 of 399 patients, and only 13% had no detectable CH. Despite a high prevalence of mutations in the most frequently mutated genes DNMT3A (165 patients) and TET2 (107 patients), mutations in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2 were associated with increased death compared with the average death rate of all patients. To avoid confounding effects, we excluded patients with DNMT3A-related, TET2-related, and other clonal haematopoiesis of indeterminate potential (CHIP)-related mutations with a VAF ≥ 2% for further analyses. Kaplan-Meier survival analyses revealed a significantly higher mortality in patients with mutations in either of the seven genes (53 patients), combined as the CH-risk gene set for CHF. Baseline patient characteristics showed no significant differences in any parameter including patient age, confounding diseases, severity of CHF, or blood cell parameters except for a reduced number of platelets in patients with mutations in the risk gene set in comparison with patients without. However, carrying a mutation in any of the risk genes remained significant after multivariate cox regression analysis (hazard ratio, 3.1; 95% confidence interval, 1.8-5.4; P < 0.001), whereas platelet numbers did not.ConclusionsSomatic mutations with low VAF in a distinct set of genes, namely, in CBL, CEBPA, EZH2, GNB1, PHF6, SMC1A, and SRSF2, are significantly associated with mortality in CHF, independently of the most prevalent CHIP-mutations in DNMT3A and TET2. Mutations in these genes are prevalent in young CHF patients and comprise an independent risk factor for the outcome of CHF, potentially providing a novel tool for risk assessment in CHF.

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Common and rare variant associations with clonal haematopoiesis phenotypes.

Publications

Common and rare variant associations with clonal haematopoiesis phenotypes.

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