Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution.
Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution.
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DOI：
10.1210/clinem/dgab877
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发表时间：
2022-03-24
期刊：
影响因子：
--
通讯作者：
Savage DB
中科院分区：
文献类型：
--
作者：
Koprulu M;Zhao Y;Wheeler E;Dong L;Rocha N;Li C;Griffin JD;Patel S;Van de Streek M;Glastonbury CA;Stewart ID;Day FR;Luan J;Bowker N;Wittemans LBL;Kerrison ND;Cai L;Lucarelli DME;Barroso I;McCarthy MI;Scott RA;Saudek V;Small KS;Wareham NJ;Semple RK;Perry JRB;O'Rahilly S;Lotta LA;Langenberg C;Savage DB
来自代谢健康的关键决定者的大规模，基于阵列的遗传研究的生物学和翻译洞察力受到将主要非编码变体与特定基因靶标联系起来的困难。涉及特定基因，但不一定表明功能的增益或丧失（LOF）是最大的治疗益处。
这项工作旨在确定与确定脂肪分布有关的基因/蛋白质。
我们结合了在英国生物库中450 562个个体中基于阵列的稀有稀有，非同义变体的全基因组分析的力量，并在184 246个个人中具有基于外显子序的稀有LOF Gene Burnen测试。
数据表明4个基因的LOF（PLIN1 [LOF变体，P = 5.86×10–7]，Insr [Lof变体，P = 6.21×10–7]，ACVR1C [LOF+中度影响变体，P = 1.68×× 10–7;中等影响变体，p = 4.57×10–7]和pde3b [lof变体，p = 1.41×10–6]）与体重指数调整后的腰围比和增加的臀肌脂肪质量相关的有益影响，而PLIN4的LOF（LOF变体，p = 5.86×10-7）对这些参数产生不利影响。 PLIN1，PDE3B和ACVR1C有利影响代谢表型（例如，甘油三酸酯[TGS]和高密度脂蛋白[HDL]胆固醇浓度）并降低了心血管疾病的风险，而PLIN4 LOF具有不良的健康后果。
这项研究可牢固地实现这些基因的脂肪分布调节，在某些情况下提供了对靶向这些分子热靶向的潜在后果的新作用。
Biological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking predominantly noncoding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss of function (LoF) would be of most therapeutic benefit. This work aimed to identify genes/proteins involved in determining fat distribution. We combined the power of genome-wide analysis of array-based rare, nonsynonymous variants in 450 562 individuals in the UK Biobank with exome-sequence-based rare LoF gene burden testing in 184 246 individuals. The data indicate that the LoF of 4 genes (PLIN1 [LoF variants, P = 5.86 × 10–7], INSR [LoF variants, P = 6.21 × 10–7], ACVR1C [LoF + moderate impact variants, P = 1.68 × 10–7; moderate impact variants, P = 4.57 × 10–7], and PDE3B [LoF variants, P = 1.41 × 10–6]) is associated with a beneficial effect on body mass index–adjusted waist-to-hip ratio and increased gluteofemoral fat mass, whereas LoF of PLIN4 (LoF variants, P = 5.86 × 10–7 adversely affects these parameters. Phenotypic follow-up suggests that LoF of PLIN1, PDE3B, and ACVR1C favorably affects metabolic phenotypes (eg, triglycerides [TGs] and high-density lipoprotein [HDL] cholesterol concentrations) and reduces the risk of cardiovascular disease, whereas PLIN4 LoF has adverse health consequences. INSR LoF is associated with lower TG and HDL levels but may increase the risk of type 2 diabetes. This study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counterintuitive insight into the potential consequences of targeting these molecules therapeutically.
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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：
5.3
作者：
DiPilato, Lisa M.;Ahmad, Faiyaz;Birnbaum, Morris J.
通讯作者：
Birnbaum, Morris J.
影响因子：
7.7
作者：
Emdin, Connor A.;Khera, Amit V.;Kathiresan, Sekar
通讯作者：
Kathiresan, Sekar