Distinction of lymphoid and myeloid clonal hematopoiesis

Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies

Krüppel-like factor 4 regulates macrophage polarization

Current paradigms suggest that two macrophage subsets, termed M1 and M2, are involved in inflammation and host defense. While the distinct functions of M1 and M2 macrophages have been intensively studied — the former are considered proinflammatory and the latter antiinflammatory — the determinants of their speciation are incompletely understood. Here we report our studies that identify Krüppel-like factor 4 (KLF4) as a critical regulator of macrophage polarization. Macrophage KLF4 expression was robustly induced in M2 macrophages and strongly reduced in M1 macrophages, observations that were recapitulated in human inflammatory paradigms in vivo. Mechanistically, KLF4 was found to cooperate with Stat6 to induce an M2 genetic program and inhibit M1 targets via sequestration of coactivators required for NF-κB activation. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. Furthermore, mice bearing myeloid-specific deletion of KLF4 exhibited delayed wound healing and were predisposed to developing diet-induced obesity, glucose intolerance, and insulin resistance. Collectively, these data identify KLF4 as what we believe to be a novel regulator of macrophage polarization

Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program.

Acknowledgements: This work was supported by funding from the Department of VA Office of Research and Development, MVP grant MVP000 and the Department of Veterans, I01-BX003362 (P.S.T.), IK2-CX001780 (S.M.D.), IK2BX005759-01 (D.K.). This publication does not represent the views of the Department of VA or the United States Government. This project was partially supported by the Baszucki Research Initiative provided to Stanford Vascular Surgery in 2022 (D.K.). S.A.L., Y.L. and Y.H.S. are supported by grants from the American Heart Association Vascular Diseases Strategically Focused Research Networks (AHA18SFRN33960114). S.A.L. is supported in part by the Jimmy and Roberta Howell Professorship in Cardiovascular Surgery at Baylor College of Medicine. P.N. is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, R01HL127564, R01HL151152) and the National Human Genome Research Institute (U01HG011719). K.G.A. is supported by grants from the National Institutes of Health (NIH; 1K08HL153937) and the American Heart Association (862032). K.P. is supported by a grant from the National Heart, Lung, and Blood Institute (5-T32HL007208-43). A.R.A. is supported by award number F30-DK120062. D.M.M. is supported by the National Heart, Lung, and Blood Institute (RO1HL62594) and the John Ritter and Remembrin’ Benjamin foundations. M.G.L. is supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the NIH–NHLBI National Research Service Award postdoctoral fellowship (T32HL007843) and the Measey Foundation. R.D. is supported by the National Institute of General Medical Sciences of the NIH (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915). J.P.P. is supported by a grant from the NIH (K08HL159346). S.B. is supported by the Wellcome Trust (225790/Z/22/Z) and the United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7). D.M.M. is supported by a grant from the NIH (R01HL109942). C.J.W. was supported by a grant from the NIH (R01HL109946). P.T.E. is supported by grants from the NIH (1RO1HL092577, 1R01HL157635, 5R01HL139731), from the American Heart Association Strategically Focused Research Networks (18SFRN34110082) and from the European Union (MAESTRIA 965286).The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size

Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size

Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program.

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection

Abstract 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