TY - JOUR T1 - Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. JF - J Am Coll Cardiol Y1 - 2016 A1 - Khera, Amit V A1 - Won, Hong-Hee A1 - Peloso, Gina M A1 - Lawson, Kim S A1 - Bartz, Traci M A1 - Deng, Xuan A1 - van Leeuwen, Elisabeth M A1 - Natarajan, Pradeep A1 - Emdin, Connor A A1 - Bick, Alexander G A1 - Morrison, Alanna C A1 - Brody, Jennifer A A1 - Gupta, Namrata A1 - Nomura, Akihiro A1 - Kessler, Thorsten A1 - Duga, Stefano A1 - Bis, Joshua C A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Psaty, Bruce A1 - Rader, Daniel J A1 - Danesh, John A1 - Schunkert, Heribert A1 - McPherson, Ruth A1 - Farrall, Martin A1 - Watkins, Hugh A1 - Lander, Eric A1 - Wilson, James G A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Merlini, Piera Angelica A1 - Ardissino, Diego A1 - Saleheen, Danish A1 - Gabriel, Stacey A1 - Kathiresan, Sekar AB -

BACKGROUND: Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.

OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.

METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.

RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.

CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.

VL - 67 IS - 22 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27050191?dopt=Abstract ER - TY - JOUR T1 - Inherited causes of clonal haematopoiesis in 97,691 whole genomes. JF - Nature Y1 - 2020 A1 - Bick, Alexander G A1 - Weinstock, Joshua S A1 - Nandakumar, Satish K A1 - Fulco, Charles P A1 - Bao, Erik L A1 - Zekavat, Seyedeh M A1 - Szeto, Mindy D A1 - Liao, Xiaotian A1 - Leventhal, Matthew J A1 - Nasser, Joseph A1 - Chang, Kyle A1 - Laurie, Cecelia A1 - Burugula, Bala Bharathi A1 - Gibson, Christopher J A1 - Lin, Amy E A1 - Taub, Margaret A A1 - Aguet, Francois A1 - Ardlie, Kristin A1 - Mitchell, Braxton D A1 - Barnes, Kathleen C A1 - Moscati, Arden A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Silverman, Edwin K A1 - Weiss, Scott T A1 - Palmer, Nicholette D A1 - Vasan, Ramachandran S A1 - Burchard, Esteban G A1 - Kardia, Sharon L R A1 - He, Jiang A1 - Kaplan, Robert C A1 - Smith, Nicholas L A1 - Arnett, Donna K A1 - Schwartz, David A A1 - Correa, Adolfo A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Konkle, Barbara A A1 - Custer, Brian A1 - Peralta, Juan M A1 - Gui, Hongsheng A1 - Meyers, Deborah A A1 - McGarvey, Stephen T A1 - Chen, Ida Yii-Der A1 - Shoemaker, M Benjamin A1 - Peyser, Patricia A A1 - Broome, Jai G A1 - Gogarten, Stephanie M A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Montasser, May E A1 - Daya, Michelle A1 - Kenny, Eimear E A1 - North, Kari E A1 - Launer, Lenore J A1 - Cade, Brian E A1 - Bis, Joshua C A1 - Cho, Michael H A1 - Lasky-Su, Jessica A1 - Bowden, Donald W A1 - Cupples, L Adrienne A1 - Mak, Angel C Y A1 - Becker, Lewis C A1 - Smith, Jennifer A A1 - Kelly, Tanika N A1 - Aslibekyan, Stella A1 - Heckbert, Susan R A1 - Tiwari, Hemant K A1 - Yang, Ivana V A1 - Heit, John A A1 - Lubitz, Steven A A1 - Johnsen, Jill M A1 - Curran, Joanne E A1 - Wenzel, Sally E A1 - Weeks, Daniel E A1 - Rao, Dabeeru C A1 - Darbar, Dawood A1 - Moon, Jee-Young A1 - Tracy, Russell P A1 - Buth, Erin J A1 - Rafaels, Nicholas A1 - Loos, Ruth J F A1 - Durda, Peter A1 - Liu, Yongmei A1 - Hou, Lifang A1 - Lee, Jiwon A1 - Kachroo, Priyadarshini A1 - Freedman, Barry I A1 - Levy, Daniel A1 - Bielak, Lawrence F A1 - Hixson, James E A1 - Floyd, James S A1 - Whitsel, Eric A A1 - Ellinor, Patrick T A1 - Irvin, Marguerite R A1 - Fingerlin, Tasha E A1 - Raffield, Laura M A1 - Armasu, Sebastian M A1 - Wheeler, Marsha M A1 - Sabino, Ester C A1 - Blangero, John A1 - Williams, L Keoki A1 - Levy, Bruce D A1 - Sheu, Wayne Huey-Herng A1 - Roden, Dan M A1 - Boerwinkle, Eric A1 - Manson, JoAnn E A1 - Mathias, Rasika A A1 - Desai, Pinkal A1 - Taylor, Kent D A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Kooperberg, Charles A1 - Laurie, Cathy C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Zhao, Hongyu A1 - Lange, Ethan A1 - Lange, Leslie A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Scheet, Paul A1 - Kitzman, Jacob O A1 - Lander, Eric S A1 - Engreitz, Jesse M A1 - Ebert, Benjamin L A1 - Reiner, Alexander P A1 - Jaiswal, Siddhartha A1 - Abecasis, Goncalo A1 - Sankaran, Vijay G A1 - Kathiresan, Sekar A1 - Natarajan, Pradeep AB -

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

VL - 586 IS - 7831 ER - TY - JOUR T1 - is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. JF - Blood Cancer Discov Y1 - 2021 A1 - Beauchamp, Ellen M A1 - Leventhal, Matthew A1 - Bernard, Elsa A1 - Hoppe, Emma R A1 - Todisco, Gabriele A1 - Creignou, Maria A1 - Gallì, Anna A1 - Castellano, Cecilia A A1 - McConkey, Marie A1 - Tarun, Akansha A1 - Wong, Waihay A1 - Schenone, Monica A1 - Stanclift, Caroline A1 - Tanenbaum, Benjamin A1 - Malolepsza, Edyta A1 - Nilsson, Björn A1 - Bick, Alexander G A1 - Weinstock, Joshua S A1 - Miller, Mendy A1 - Niroula, Abhishek A1 - Dunford, Andrew A1 - Taylor-Weiner, Amaro A1 - Wood, Timothy A1 - Barbera, Alex A1 - Anand, Shankara A1 - Psaty, Bruce M A1 - Desai, Pinkal A1 - Cho, Michael H A1 - Johnson, Andrew D A1 - Loos, Ruth A1 - MacArthur, Daniel G A1 - Lek, Monkol A1 - Neuberg, Donna S A1 - Lage, Kasper A1 - Carr, Steven A A1 - Hellstrom-Lindberg, Eva A1 - Malcovati, Luca A1 - Papaemmanuil, Elli A1 - Stewart, Chip A1 - Getz, Gad A1 - Bradley, Robert K A1 - Jaiswal, Siddhartha A1 - Ebert, Benjamin L AB -

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, , as well as in , , and . We also identified these mutations at low frequency in myelodysplastic syndrome patients. edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage and increased genome-wide intron retention. mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

VL - 2 IS - 5 ER - TY - JOUR T1 - Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. JF - J Am Coll Cardiol Y1 - 2021 A1 - Yu, Bing A1 - Roberts, Mary B A1 - Raffield, Laura M A1 - Zekavat, Seyedeh Maryam A1 - Nguyen, Ngoc Quynh H A1 - Biggs, Mary L A1 - Brown, Michael R A1 - Griffin, Gabriel A1 - Desai, Pinkal A1 - Correa, Adolfo A1 - Morrison, Alanna C A1 - Shah, Amil M A1 - Niroula, Abhishek A1 - Uddin, Md Mesbah A1 - Honigberg, Michael C A1 - Ebert, Benjamin L A1 - Psaty, Bruce M A1 - Whitsel, Eric A A1 - Manson, JoAnn E A1 - Kooperberg, Charles A1 - Bick, Alexander G A1 - Ballantyne, Christie M A1 - Reiner, Alex P A1 - Natarajan, Pradeep A1 - Eaton, Charles B KW - Aged KW - Clonal Hematopoiesis KW - Correlation of Data KW - Demography KW - DNA-Binding Proteins KW - Female KW - Heart Failure KW - Humans KW - Janus Kinase 2 KW - Male KW - Middle Aged KW - Mutation KW - Proportional Hazards Models KW - Proto-Oncogene Proteins KW - Repressor Proteins KW - Risk Factors KW - Stroke Volume KW - Ventricular Dysfunction, Left KW - Whole Exome Sequencing AB -

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.

METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

VL - 78 IS - 1 ER - TY - JOUR T1 - Clonal Hematopoiesis Is Associated With Higher Risk of Stroke. JF - Stroke Y1 - 2022 A1 - Bhattacharya, Romit A1 - Zekavat, Seyedeh M A1 - Haessler, Jeffrey A1 - Fornage, Myriam A1 - Raffield, Laura A1 - Uddin, Md Mesbah A1 - Bick, Alexander G A1 - Niroula, Abhishek A1 - Yu, Bing A1 - Gibson, Christopher A1 - Griffin, Gabriel A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Longstreth, William T A1 - Bis, Joshua C A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Tracy, Russell P A1 - Correa, Adolfo A1 - Seshadri, Sudha A1 - Johnson, Andrew A1 - Collins, Jason M A1 - Hayden, Kathleen M A1 - Madsen, Tracy E A1 - Ballantyne, Christie M A1 - Jaiswal, Siddhartha A1 - Ebert, Benjamin L A1 - Kooperberg, Charles A1 - Manson, JoAnn E A1 - Whitsel, Eric A A1 - Natarajan, Pradeep A1 - Reiner, Alexander P AB -

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.

METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (, , and ) with any stroke, ischemic stroke, and hemorrhagic stroke.

RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, showed the strongest association with total stroke and ischemic stroke, whereas and were each associated with increased risk of hemorrhagic stroke.

CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

VL - 53 IS - 3 ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population. JF - Am J Kidney Dis Y1 - 2022 A1 - Kestenbaum, Bryan A1 - Bick, Alexander G A1 - Vlasschaert, Caitlyn A1 - Rauh, Michael J A1 - Lanktree, Matthew B A1 - Franceschini, Nora A1 - Shoemaker, Moore B A1 - Harris, Raymond C A1 - Psaty, Bruce M A1 - Köttgen, Anna A1 - Natarajan, Pradeep A1 - Robinson-Cohen, Cassianne AB -

RATIONALE & OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.

EXPOSURE: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.

OUTCOME: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.

ANALYTICAL APPROACH: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.

RESULTS: The median baseline eGFR was 84mL/min/1.73m. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m, of age above or below 60 years, or with or without diabetes.

LIMITATIONS: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.

CONCLUSIONS: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.

ER - TY - JOUR T1 - Large-scale genome-wide association study of coronary artery disease in genetically diverse populations. JF - Nat Med Y1 - 2022 A1 - Tcheandjieu, Catherine A1 - Zhu, Xiang A1 - Hilliard, Austin T A1 - Clarke, Shoa L A1 - Napolioni, Valerio A1 - Ma, Shining A1 - Lee, Kyung Min A1 - Fang, Huaying A1 - Chen, Fei A1 - Lu, Yingchang A1 - Tsao, Noah L A1 - Raghavan, Sridharan A1 - Koyama, Satoshi A1 - Gorman, Bryan R A1 - Vujkovic, Marijana A1 - Klarin, Derek A1 - Levin, Michael G A1 - Sinnott-Armstrong, Nasa A1 - Wojcik, Genevieve L A1 - Plomondon, Mary E A1 - Maddox, Thomas M A1 - Waldo, Stephen W A1 - Bick, Alexander G A1 - Pyarajan, Saiju A1 - Huang, Jie A1 - Song, Rebecca A1 - Ho, Yuk-Lam A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - Haessler, Jeffrey A1 - Loos, Ruth J F A1 - Do, Ron A1 - Verbanck, Marie A1 - Chaudhary, Kumardeep A1 - North, Kari E A1 - Avery, Christy L A1 - Graff, Mariaelisa A1 - Haiman, Christopher A A1 - Le Marchand, Loïc A1 - Wilkens, Lynne R A1 - Bis, Joshua C A1 - Leonard, Hampton A1 - Shen, Botong A1 - Lange, Leslie A A1 - Giri, Ayush A1 - Dikilitas, Ozan A1 - Kullo, Iftikhar J A1 - Stanaway, Ian B A1 - Jarvik, Gail P A1 - Gordon, Adam S A1 - Hebbring, Scott A1 - Namjou, Bahram A1 - Kaufman, Kenneth M A1 - Ito, Kaoru A1 - Ishigaki, Kazuyoshi A1 - Kamatani, Yoichiro A1 - Verma, Shefali S A1 - Ritchie, Marylyn D A1 - Kember, Rachel L A1 - Baras, Aris A1 - Lotta, Luca A A1 - Kathiresan, Sekar A1 - Hauser, Elizabeth R A1 - Miller, Donald R A1 - Lee, Jennifer S A1 - Saleheen, Danish A1 - Reaven, Peter D A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Natarajan, Pradeep A1 - Huffman, Jennifer E A1 - Voight, Benjamin F A1 - Rader, Daniel J A1 - Chang, Kyong-Mi A1 - Lynch, Julie A A1 - Damrauer, Scott M A1 - Wilson, Peter W F A1 - Tang, Hua A1 - Sun, Yan V A1 - Tsao, Philip S A1 - O'Donnell, Christopher J A1 - Assimes, Themistocles L KW - Coronary Artery Disease KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

VL - 28 IS - 8 ER - TY - JOUR T1 - Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. JF - Nature Y1 - 2023 A1 - Weinstock, Joshua S A1 - Gopakumar, Jayakrishnan A1 - Burugula, Bala Bharathi A1 - Uddin, Md Mesbah A1 - Jahn, Nikolaus A1 - Belk, Julia A A1 - Bouzid, Hind A1 - Daniel, Bence A1 - Miao, Zhuang A1 - Ly, Nghi A1 - Mack, Taralynn M A1 - Luna, Sofia E A1 - Prothro, Katherine P A1 - Mitchell, Shaneice R A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Sinner, Moritz F A1 - von Falkenhausen, Aenne S A1 - Kääb, Stefan A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Hou, Lifang A1 - Lloyd-Jones, Donald M A1 - Redline, Susan A1 - Cade, Brian E A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - DeMeo, Dawn L A1 - Vasan, Ramachandran S A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - He, Jiang A1 - Rienstra, Michiel A1 - van der Harst, Pim A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Cutler, Michael J A1 - Knight, Stacey A1 - Muhlestein, J Brent A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Smith, J Gustav A1 - Melander, Olle A1 - Nilsson, Peter M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - McGarvey, Stephen A1 - Williams, L Keoki A1 - Xiao, Shujie A1 - Yang, Mao A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Marcus, Gregory M A1 - Kane, John P A1 - Pullinger, Clive R A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan M A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Zhou, Ying A1 - Manson, JoAnn E A1 - Desai, Pinkal A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Satpathy, Ansuman T A1 - Natarajan, Pradeep A1 - Kitzman, Jacob O A1 - Whitsel, Eric A A1 - Reiner, Alexander P A1 - Bick, Alexander G A1 - Jaiswal, Siddhartha KW - Alleles KW - Animals KW - Clonal Hematopoiesis KW - Genome-Wide Association Study KW - Hematopoiesis KW - Hematopoietic Stem Cells KW - Humans KW - Mice KW - Mutation KW - Promoter Regions, Genetic AB -

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

VL - 616 IS - 7958 ER - TY - JOUR T1 - Clonal hematopoiesis is associated with protection from Alzheimer's disease. JF - Nat Med Y1 - 2023 A1 - Bouzid, Hind A1 - Belk, Julia A A1 - Jan, Max A1 - Qi, Yanyan A1 - Sarnowski, Chloe A1 - Wirth, Sara A1 - Ma, Lisa A1 - Chrostek, Matthew R A1 - Ahmad, Herra A1 - Nachun, Daniel A1 - Yao, Winnie A1 - Beiser, Alexa A1 - Bick, Alexander G A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Longstreth, William T A1 - Lopez, Oscar L A1 - Natarajan, Pradeep A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Weinstock, Joshua A1 - Larson, Eric B A1 - Crane, Paul K A1 - Keene, C Dirk A1 - Seshadri, Sudha A1 - Satpathy, Ansuman T A1 - Montine, Thomas J A1 - Jaiswal, Siddhartha AB -

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

VL - 29 IS - 7 ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk. JF - Diabetes Care Y1 - 2023 A1 - Tobias, Deirdre K A1 - Manning, Alisa K A1 - Wessel, Jennifer A1 - Raghavan, Sridharan A1 - Westerman, Kenneth E A1 - Bick, Alexander G A1 - DiCorpo, Daniel A1 - Whitsel, Eric A A1 - Collins, Jason A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Dupuis, Josée A1 - Goodarzi, Mark O A1 - Guo, Xiuqing A1 - Howard, Barbara A1 - Lange, Leslie A A1 - Liu, Simin A1 - Raffield, Laura M A1 - Reiner, Alex P A1 - Rich, Stephen S A1 - Taylor, Kent D A1 - Tinker, Lesley A1 - Wilson, James G A1 - Wu, Peitao A1 - Carson, April P A1 - Vasan, Ramachandran S A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Rotter, Jerome I A1 - Meigs, James A1 - Manson, JoAnn E AB -

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.

RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis.

RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI = 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI = 1.05, 2.08) and ASXL1 (HR 1.76; CI = 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI = 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses.

CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

ER - TY - JOUR T1 - Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury. JF - medRxiv Y1 - 2023 A1 - Vlasschaert, Caitlyn A1 - Robinson-Cohen, Cassianne A1 - Kestenbaum, Bryan A1 - Silver, Samuel A A1 - Chen, Jian-Chun A1 - Akwo, Elvis A1 - Bhatraju, Pavan K A1 - Zhang, Ming-Zhi A1 - Cao, Shirong A1 - Jiang, Ming A1 - Wang, Yinqiu A1 - Niu, Aolei A1 - Siew, Edward A1 - Kramer, Holly J A1 - Köttgen, Anna A1 - Franceschini, Nora A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Coresh, Josef A1 - Ballantyne, Christie M A1 - Boerwinkle, Eric A1 - Grams, Morgan A1 - Lanktree, Matthew B A1 - Rauh, Michael J A1 - Harris, Raymond C A1 - Bick, Alexander G AB -

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as and and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than (HR: 1.49, 95% CI: 1.37-1.61, p<0.0001). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non- CHIP was more common among those with a non-resolving pattern of injury (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in -CHIP mice. Kidney macrophage infiltration was markedly increased in -CHIP mice and -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.

ER - TY - JOUR T1 - Determinants of mosaic chromosomal alteration fitness. JF - medRxiv Y1 - 2023 A1 - Pershad, Yash A1 - Mack, Taralynn A1 - Poisner, Hannah A1 - Jakubek, Yasminka A A1 - Stilp, Adrienne M A1 - Mitchell, Braxton D A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Loos, Ruth J A1 - Chami, Nathalie A1 - Wang, Zhe A1 - Barnes, Kathleen A1 - Pankratz, Nathan A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Shojaie, Ali A1 - Silverman, Edwin K A1 - Cho, Michael H A1 - Yun, Jeong A1 - DeMeo, Dawn A1 - Levy, Daniel A1 - Johnson, Andrew A1 - Mathias, Rasika A1 - Taub, Margaret A1 - Arnett, Donna A1 - North, Kari A1 - Raffield, Laura M A1 - Carson, April A1 - Doyle, Margaret F A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Guo, Xiuqing A1 - Cox, Nancy A1 - Roden, Dan M A1 - Franceschini, Nora A1 - Desai, Pinkal A1 - Reiner, Alex A1 - Auer, Paul L A1 - Scheet, Paul A1 - Jaiswal, Siddhartha A1 - Weinstock, Joshua S A1 - Bick, Alexander G AB -

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

ER - TY - JOUR T1 - The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. JF - Sci Adv Y1 - 2023 A1 - Weinstock, Joshua S A1 - Laurie, Cecelia A A1 - Broome, Jai G A1 - Taylor, Kent D A1 - Guo, Xiuqing A1 - Shuldiner, Alan R A1 - O'Connell, Jeffrey R A1 - Lewis, Joshua P A1 - Boerwinkle, Eric A1 - Barnes, Kathleen C A1 - Chami, Nathalie A1 - Kenny, Eimear E A1 - Loos, Ruth J F A1 - Fornage, Myriam A1 - Redline, Susan A1 - Cade, Brian E A1 - Gilliland, Frank D A1 - Chen, Zhanghua A1 - Gauderman, W James A1 - Kumar, Rajesh A1 - Grammer, Leslie A1 - Schleimer, Robert P A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Silverman, Edwin K A1 - Yun, Jeong H A1 - Qiao, Dandi A1 - Weiss, Scott T A1 - Lasky-Su, Jessica A1 - DeMeo, Dawn L A1 - Palmer, Nicholette D A1 - Freedman, Barry I A1 - Bowden, Donald W A1 - Cho, Michael H A1 - Vasan, Ramachandran S A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Becker, Lewis C A1 - Kardia, Sharon A1 - He, Jiang A1 - Kaplan, Robert A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Wiggins, Kerri L A1 - Arnett, Donna K A1 - Irvin, Marguerite R A1 - Tiwari, Hemant A1 - Correa, Adolfo A1 - Raffield, Laura M A1 - Gao, Yan A1 - de Andrade, Mariza A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Manichaikul, Ani W A1 - Konkle, Barbara A A1 - Johnsen, Jill M A1 - Wheeler, Marsha M A1 - Custer, Brian S A1 - Duggirala, Ravindranath A1 - Curran, Joanne E A1 - Blangero, John A1 - Gui, Hongsheng A1 - Xiao, Shujie A1 - Williams, L Keoki A1 - Meyers, Deborah A A1 - Li, Xingnan A1 - Ortega, Victor A1 - McGarvey, Stephen A1 - Gu, C Charles A1 - Chen, Yii-Der Ida A1 - Lee, Wen-Jane A1 - Shoemaker, M Benjamin A1 - Darbar, Dawood A1 - Roden, Dan A1 - Albert, Christine A1 - Kooperberg, Charles A1 - Desai, Pinkal A1 - Blackwell, Thomas W A1 - Abecasis, Goncalo R A1 - Smith, Albert V A1 - Kang, Hyun M A1 - Mathias, Rasika A1 - Natarajan, Pradeep A1 - Jaiswal, Siddhartha A1 - Reiner, Alexander P A1 - Bick, Alexander G KW - Germ-Line Mutation KW - Hematopoiesis KW - Humans KW - Middle Aged KW - Mutation KW - Mutation, Missense KW - Phenotype AB -

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

VL - 9 IS - 17 ER - TY - JOUR T1 - Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. JF - Nat Genet Y1 - 2023 A1 - Jakubek, Yasminka A A1 - Zhou, Ying A1 - Stilp, Adrienne A1 - Bacon, Jason A1 - Wong, Justin W A1 - Ozcan, Zuhal A1 - Arnett, Donna A1 - Barnes, Kathleen A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Carson, April P A1 - Chasman, Daniel I A1 - Chen, Jiawen A1 - Cho, Michael A1 - Conomos, Matthew P A1 - Cox, Nancy A1 - Doyle, Margaret F A1 - Fornage, Myriam A1 - Guo, Xiuqing A1 - Kardia, Sharon L R A1 - Lewis, Joshua P A1 - Loos, Ruth J F A1 - Ma, Xiaolong A1 - Machiela, Mitchell J A1 - Mack, Taralynn M A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Mychaleckyj, Josyf C A1 - North, Kari A1 - Pankratz, Nathan A1 - Peyser, Patricia A A1 - Preuss, Michael H A1 - Psaty, Bruce A1 - Raffield, Laura M A1 - Vasan, Ramachandran S A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Silverman, Edwin K A1 - Smith, Jennifer A A1 - Smith, Aaron P A1 - Taub, Margaret A1 - Taylor, Kent D A1 - Yun, Jeong A1 - Li, Yun A1 - Desai, Pinkal A1 - Bick, Alexander G A1 - Reiner, Alexander P A1 - Scheet, Paul A1 - Auer, Paul L KW - Black People KW - Genome, Human KW - Genome-Wide Association Study KW - Hispanic or Latino KW - Humans KW - Mosaicism KW - Precision Medicine AB -

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

VL - 55 IS - 11 ER -