Inherited causes of clonal haematopoiesis in 97,691 whole genomes.
Inherited causes of clonal haematopoiesis in 97,691 whole genomes.
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DOI：
10.1038/s41586-020-2819-2
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Natarajan P
中科院分区：
文献类型：
--
作者：
Bick AG;Weinstock JS;Nandakumar SK;Fulco CP;Bao EL;Zekavat SM;Szeto MD;Liao X;Leventhal MJ;Nasser J;Chang K;Laurie C;Burugula BB;Gibson CJ;Lin AE;Taub MA;Aguet F;Ardlie K;Mitchell BD;Barnes KC;Moscati A;Fornage M;Redline S;Psaty BM;Silverman EK;Weiss ST;Palmer ND;Vasan RS;Burchard EG;Kardia SLR;He J;Kaplan RC;Smith NL;Arnett DK;Schwartz DA;Correa A;de Andrade M;Guo X;Konkle BA;Custer B;Peralta JM;Gui H;Meyers DA;McGarvey ST;Chen IY;Shoemaker MB;Peyser PA;Broome JG;Gogarten SM;Wang FF;Wong Q;Montasser ME;Daya M;Kenny EE;North KE;Launer LJ;Cade BE;Bis JC;Cho MH;Lasky-Su J;Bowden DW;Cupples LA;Mak ACY;Becker LC;Smith JA;Kelly TN;Aslibekyan S;Heckbert SR;Tiwari HK;Yang IV;Heit JA;Lubitz SA;Johnsen JM;Curran JE;Wenzel SE;Weeks DE;Rao DC;Darbar D;Moon JY;Tracy RP;Buth EJ;Rafaels N;Loos RJF;Durda P;Liu Y;Hou L;Lee J;Kachroo P;Freedman BI;Levy D;Bielak LF;Hixson JE;Floyd JS;Whitsel EA;Ellinor PT;Irvin MR;Fingerlin TE;Raffield LM;Armasu SM;Wheeler MM;Sabino EC;Blangero J;Williams LK;Levy BD;Sheu WH;Roden DM;Boerwinkle E;Manson JE;Mathias RA;Desai P;Taylor KD;Johnson AD;NHLBI Trans-Omics for Precision Medicine Consortium;Auer PL;Kooperberg C;Laurie CC;Blackwell TW;Smith AV;Zhao H;Lange E;Lange L;Rich SS;Rotter JI;Wilson JG;Scheet P;Kitzman JO;Lander ES;Engreitz JM;Ebert BL;Reiner AP;Jaiswal S;Abecasis G;Sankaran VG;Kathiresan S;Natarajan P
年龄是大多数慢性人类疾病的主要风险因素;然而，衰老赋予这种风险的机制在很大程度上是未知的。最近，在再生造血干细胞群体中与年龄相关的体细胞突变的获得导致克隆扩增与血液癌症和冠心病两者相关，这种现象被称为“不确定潜能的克隆造血”（CHIP）。同时进行生殖系和体细胞全基因组序列分析现在提供了确定CHIP根本原因的机会。在这里，我们分析了来自NHLBI TOPMed计划中不同血统的97，691名参与者的高覆盖率全基因组序列，并确定了4，229名CHIP个体。我们确定了不同CHIP基因与血细胞、脂质和炎症特征的相关性。一组全基因组种系遗传变异的关联确定了三个与CHIP状态相关的遗传基因座，包括TET 2处的一个非洲血统特异性基因座。TET 2种系基因座的计算机信息体外评价鉴定了一种破坏TET 2远端增强子的致病变体，导致造血干细胞自我更新增加。总的来说，我们观察到生殖系遗传变异通过克隆造血特异性机制和导致组织间体细胞突变的共享机制来塑造造血干细胞功能，从而导致CHIP。
Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown. Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations leading to clonal expansion was associated with both hematologic cancer and coronary heart disease, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP). Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer resulting in increased hematopoietic stem cell self-renewal. Overall, we observe that germline genetic variation shapes hematopoietic stem cell function leading to CHIP through mechanisms that are both specific to clonal hematopoiesis and shared mechanisms leading to somatic mutations across tissues.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
DOI：
10.1093/infdis/jiv277
发表时间：
2015-11-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Horvath S;Levine AJ
通讯作者：
Levine AJ
影响因子：
30.8
作者：
Hu, Yiming;Li, Mo;Yu, Lei
通讯作者：
Yu, Lei
影响因子：
30.8
作者：
Fulco, Charles P.;Nasser, Joseph;Engreitz, Jesse M.
通讯作者：
Engreitz, Jesse M.