Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.
Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.
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DOI：
10.1038/s41467-022-32398-7
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发表时间：
2022-08-23
影响因子：
16.6
通讯作者：
Lotta, Luca A.
中科院分区：
文献类型：
--
作者：
Akbari, Parsa;Sosina, Olukayode A.;Bovijn, Jonas;Landheer, Karl;Nielsen, Jonas B.;Kim, Minhee;Aykul, Senem;De, Tanima;Haas, Mary E.;Hindy, George;Lin, Nan;Dinsmore, Ian R.;Luo, Jonathan Z.;Hectors, Stefanie;Geraghty, Benjamin;Germino, Mary;Panagis, Lampros;Parasoglou, Prodromos;Walls, Johnathon R.;Halasz, Gabor;Atwal, Gurinder S.;Jones, Marcus;LeBlanc, Michelle G.;Still, Christopher D.;Carey, David J.;Giontella, Alice;Orho-Melander, Marju;Berumen, Jaime;Kuri-Morales, Pablo;Alegre-Diaz, Jesus;Torres, Jason M.;Emberson, Jonathan R.;Collins, Rory;Rader, Daniel J.;Zambrowicz, Brian;Murphy, Andrew J.;Balasubramanian, Suganthi;Overton, John D.;Reid, Jeffrey G.;Shuldiner, Alan R.;Cantor, Michael;Abecasis, Goncalo R.;Ferreira, Manuel A. R.;Sleeman, Mark W.;Gusarova, Viktoria;Altarejos, Judith;Harris, Charles;Economides, Aris N.;Idone, Vincent;Karalis, Katia;Della Gatta, Giusy;Mirshahi, Tooraj;Yancopoulos, George D.;Melander, Olle;Marchini, Jonathan;Tapia-Conyer, Roberto;Locke, Adam E.;Baras, Aris;Verweij, Niek;Lotta, Luca A.
身体脂肪分布是心脏代谢疾病的一个主要的、可遗传的危险因素，与总体肥胖无关。通过对来自英国、瑞典和墨西哥的618，375名个体（包括160，058名非欧洲人）进行外显子组测序，我们确定了16个与脂肪分布相关的基因。我们显示，与精细映射的常见等位基因相比，脂肪分布相关的罕见编码变体的影响大6倍，脂肪组织中表达的基因和部分脂肪营养不良的致病基因的富集，以及性别二态性的证据。我们描述了INHBE中杂合蛋白截短突变与有利的脂肪分布（p = 1.8 × 10−09）、有利的代谢特征和2型糖尿病保护（降低约28%的几率; p = 0.004）的相关性，INHBE编码激活素家族的循环生长因子，在肝细胞中高度特异性表达。我们的研究结果表明，Escherbin βE是一种肝脏表达的脂肪储存负调节因子，其阻断可能对脂肪分布相关的代谢疾病有益。脂肪分布与心脏代谢疾病有关，尽管它的研究不如总体肥胖。在一项多祖先外显子组测序研究中，作者确定了INHBE中预测的功能丧失突变与有利的脂肪分布和2型糖尿病保护相关。
Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10−09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease. Fat distribution is associated with cardiometabolic disease, although it has been less well studied than overall obesity. In a multiancestry exome-sequencing study, the authors identified predicted loss-of-function mutations in INHBE associated with favorable fat distribution and protection from type 2 diabetes.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
腰围比与心脏代谢性状，2型糖尿病和冠状动脉疾病的遗传关联。
DOI：
10.1001/jama.2016.21042
发表时间：
2017-02-14
期刊：
JAMA
影响因子：
--
作者：
Emdin CA;Khera AV;Natarajan P;Klarin D;Zekavat SM;Hsiao AJ;Kathiresan S
通讯作者：
Kathiresan S
影响因子：
56.9
作者：
Akbari, Parsa;Gilani, Ankit;Sosina, Olukayode;Kosmicki, Jack A.;Khrimian, Lori;Fang, Yi-Ya;Persaud, Trikaldarshi;Garcia, Victor;Sun, Dylan;Li, Alexander;Mbatchou, Joelle;Locke, Adam E.;Benner, Christian;Verweij, Niek;Lin, Nan;Hossain, Sakib;Agostinucci, Kevin;Pascale, Jonathan, V;Dirice, Ercument;Dunn, Michael;Kraus, William E.;Shah, Svati H.;Chen, Yii-Der, I;Rotter, Jerome, I;Rader, Daniel J.;Melander, Olle;Still, Christopher D.;Mirshahi, Tooraj;Carey, David J.;Berumen-Campos, Jaime;Kuri-Morales, Pablo;Alegre-Diaz, Jesus;Torres, Jason M.;Emberson, Jonathan R.;Collins, Rory;Balasubramanian, Suganthi;Hawes, Alicia;Jones, Marcus;Zambrowicz, Brian;Murphy, Andrew J.;Paulding, Charles;Coppola, Giovanni;Overton, John D.;Reid, Jeffrey G.;Shuldiner, Alan R.;Cantor, Michael;Kang, Hyun M.;Abecasis, Goncalo R.;Karalis, Katia;Economides, Aris N.;Marchini, Jonathan;Yancopoulos, George D.;Sleeman, Mark W.;Altarejos, Judith;Della Gatta, Giusy;Tapia-Conyer, Roberto;Schwartzman, Michal L.;Baras, Aris;Ferreira, Manuel A. R.;Lotta, Luca A.
通讯作者：
Lotta, Luca A.
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
64.5
作者：
Belbin, Gillian M.;Cullina, Sinead;Kenny, Eimear E.
通讯作者：
Kenny, Eimear E.