%0 Journal Article %J Nature %D 2023 %T Author Correction: Clonal haematopoiesis and risk of chronic liver disease. %A Wong, Waihay J %A Emdin, Connor %A Bick, Alexander G %A Zekavat, Seyedeh M %A Niroula, Abhishek %A Pirruccello, James P %A Dichtel, Laura %A Griffin, Gabriel %A Uddin, Md Mesbah %A Gibson, Christopher J %A Kovalcik, Veronica %A Lin, Amy E %A McConkey, Marie E %A Vromman, Amelie %A Sellar, Rob S %A Kim, Peter G %A Agrawal, Mridul %A Weinstock, Joshua %A Long, Michelle T %A Yu, Bing %A Banerjee, Rajarshi %A Nicholls, Rowan C %A Dennis, Andrea %A Kelly, Matt %A Loh, Po-Ru %A McCarroll, Steve %A Eric Boerwinkle %A Vasan, Ramachandran S %A Jaiswal, Siddhartha %A Johnson, Andrew D %A Chung, Raymond T %A Corey, Kathleen %A Levy, Daniel %A Ballantyne, Christie %A Ebert, Benjamin L %A Natarajan, Pradeep %B Nature %V 619 %P E47 %8 2023 Jul %G eng %N 7970 %1 https://www.ncbi.nlm.nih.gov/pubmed/37400552?dopt=Abstract %R 10.1038/s41586-023-06375-z %0 Journal Article %J Nature %D 2023 %T Clonal haematopoiesis and risk of chronic liver disease. %A Wong, Waihay J %A Emdin, Connor %A Bick, Alexander G %A Zekavat, Seyedeh M %A Niroula, Abhishek %A Pirruccello, James P %A Dichtel, Laura %A Griffin, Gabriel %A Uddin, Md Mesbah %A Gibson, Christopher J %A Kovalcik, Veronica %A Lin, Amy E %A McConkey, Marie E %A Vromman, Amelie %A Sellar, Rob S %A Kim, Peter G %A Agrawal, Mridul %A Weinstock, Joshua %A Long, Michelle T %A Yu, Bing %A Banerjee, Rajarshi %A Nicholls, Rowan C %A Dennis, Andrea %A Kelly, Matt %A Loh, Po-Ru %A McCarroll, Steve %A Eric Boerwinkle %A Vasan, Ramachandran S %A Jaiswal, Siddhartha %A Johnson, Andrew D %A Chung, Raymond T %A Corey, Kathleen %A Levy, Daniel %A Ballantyne, Christie %A Ebert, Benjamin L %A Natarajan, Pradeep %K Animals %K Clonal Hematopoiesis %K Disease Progression %K Disease Susceptibility %K Hepatitis %K Inflammation %K Liver Cirrhosis %K Mice %K Non-alcoholic Fatty Liver Disease %K Odds Ratio %X

Chronic liver disease is a major public health burden worldwide. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.

%B Nature %V 616 %P 747-754 %8 2023 Apr %G eng %N 7958 %1 https://www.ncbi.nlm.nih.gov/pubmed/37046084?dopt=Abstract %R 10.1038/s41586-023-05857-4 %0 Journal Article %J Nature %D 2021 %T Author Correction: Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Niroula, Abhishek %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Eric Boerwinkle %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %B Nature %V 591 %P E27 %8 2021 Mar %G eng %N 7851 %1 https://www.ncbi.nlm.nih.gov/pubmed/33707633?dopt=Abstract %R 10.1038/s41586-021-03280-1 %0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Eric Boerwinkle %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %K Adult %K Africa %K Aged %K Aged, 80 and over %K alpha Karyopherins %K Black People %K Cell Self Renewal %K Clonal Hematopoiesis %K Dioxygenases %K DNA-Binding Proteins %K Female %K Genetic Predisposition to Disease %K Genome, Human %K Germ-Line Mutation %K Hematopoietic Stem Cells %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Precision Medicine %K Proto-Oncogene Proteins %K Tripartite Motif Proteins %K United States %K Whole Genome Sequencing %X

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.

%B Nature %V 586 %P 763-768 %8 2020 Oct %G eng %N 7831 %1 https://www.ncbi.nlm.nih.gov/pubmed/33057201?dopt=Abstract %R 10.1038/s41586-020-2819-2