Alnylam Pharmaceuticals, Cambridge, MA, USA.
Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA.
Nat Commun. 2022 Jul 27;13(1):4319. doi: 10.1038/s41467-022-31757-8.
Identifying genetic variants associated with lower waist-to-hip ratio can reveal new therapeutic targets for abdominal obesity. We use exome sequences from 362,679 individuals to identify genes associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Predicted loss of function (pLOF) variants in INHBE associate with lower WHRadjBMI and this association replicates in data from AMP-T2D-GENES. INHBE encodes a secreted protein, the hepatokine activin E. In vitro characterization of the most common INHBE pLOF variant in our study, indicates an in-frame deletion resulting in a 90% reduction in secreted protein levels. We detect associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution. These findings highlight activin E as a potential therapeutic target for abdominal obesity, a phenotype linked to cardiometabolic disease.
鉴定与较低腰臀比相关的遗传变异可以揭示腹部肥胖的新治疗靶点。我们使用来自 362679 个人的外显子组序列来鉴定与腰臀比（BMI 调整后，WHRadjBMI，与 2 型糖尿病和冠心病有因果关系的腹部脂肪替代物）相关的基因。INHBE 中的预测功能丧失（pLOF）变异与较低的 WHRadjBMI 相关，并且这种关联在 AMP-T2D-GENES 的数据中得到了复制。INHBE 编码一种分泌蛋白，即肝细胞生长因子 E。我们对研究中最常见的 INHBE pLOF 变异体进行了体外特征分析，表明这是一种框内缺失，导致分泌蛋白水平降低 90%。我们检测到与 ACVR1C 中变体的较低 WHRadjBMI 相关，该变体编码激活素受体，进一步强调了激活素在调节脂肪分布中的作用。这些发现突出了激活素 E 作为腹部肥胖的潜在治疗靶点的作用，腹部肥胖是一种与心脏代谢疾病相关的表型。
