Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.
Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.
复制标题
分析人类敲除以验证GPR151作为减少体重指数的治疗靶标。
DOI：
10.1371/journal.pgen.1010093
复制
发表时间：
2022-04
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
为了遏制肥胖的流行，需要持续降低身体质量指数(BMI)的新药物靶点。肥胖症影响着全球6.5亿人，是心血管和代谢性疾病和死亡的原因驱动因素。以前的研究报道，GPR151的Arg95Ter无义变体，一种孤立的G蛋白偶联受体，与减少BMI和降低2型糖尿病(T2D)的风险有关。在这里，我们用巴基斯坦基因组资源(PGR)进一步研究GPR151，这是世界上最大的人类纯合子功能丧失携带者(基因敲除)外显组生物库之一。在PGR参与者中，我们发现了11个可能的GPR151功能丧失(PLOF)变异，其中3个纯合子(Arg95Ter、Tyr99Ter和Phe175LeufsTer7)存在，累积等位基因频率为2.2%。我们在体外确认这些等位基因为功能丧失。我们测试GPR151 PLOF是否与BMI、T2D或其他代谢特征相关，发现完全敲除人类的GPR151缺陷与这些特征的临床显著差异无关。与GPR151+/+小鼠相比，GPR151-/-小鼠在正常饮食下的体重没有差异，而在高脂饮食下的体重更高。总之，我们的发现表明，GPR151拮抗剂并不是治疗肥胖症的令人信服的治疗方法。人类遗传学研究可以为治疗干预提供令人信服的目标。虽然一些治疗靶点，如PCSK9，是基于广泛的基因验证，但许多其他的是基于与未知后果的变体的较弱的关联，需要进一步的验证。最近的出版物报道了GPR151功能丧失与低体重指数(BMI)之间的关系，这增加了抑制GPR151用于治疗肥胖和代谢综合征的可能性。为了评估GPR151与BMI之间的关系，我们(1)鉴定并实验证实了巴基斯坦基因组资源(PGR)生物库中存在的功能缺失变种，巴基斯坦基因组资源(PGR)生物库是世界上最大的人类基因“敲除”生物库之一，(2)我们单独分析了这些功能丧失变种，并在负荷测试中分析了这些功能丧失变种与BMI和其他代谢特征或疾病的关联，以及(3)验证了我们的发现在缺乏GPR151的小鼠中的进化保守性。我们观察到GPR151的缺失不会在临床相关的程度上影响BMI，并得出结论，抑制GPR151可能在治疗肥胖症方面无效。
Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity. Human genetics studies can provide compelling targets for therapeutic intervention. While some therapeutic targets, such as PCSK9, are based on extensive genetic validation, many others are based on weaker associations with variants of unknown consequence that require further validation. Recent publications reported associations between loss of GPR151 function and low body mass index (BMI), raising the possibility of inhibiting GPR151 for the treatment of obesity and metabolic syndromes. To evaluate the relationship between GPR151 and BMI, we (1) identified and experimentally confirmed loss-of-function variants present in the Pakistan Genome Resource (PGR) biobank, one of the world’s largest biobanks of human gene “knockouts”, (2) analyzed these loss-of-function variants individually and in burden tests for association with BMI and other metabolic traits or diseases, and (3) verified the evolutionary conservation of our findings in mice lacking Gpr151. We observe that GPR151 loss does not affect BMI to a clinically relevant extent and conclude that inhibiting GPR151 may not be effective at treating obesity.
登录
查看更多内容
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
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：
Krude, H;Biebermann, H;Grüters, A
通讯作者：
Grüters, A
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
64.8
作者：
Smemo, Scott;Tena, Juan J.;Kim, Kyoung-Han;Gamazon, Eric R.;Sakabe, Noboru J.;Gomez-Marin, Carlos;Aneas, Ivy;Credidio, Flavia L.;Sobreira, Debora R.;Wasserman, Nora F.;Lee, Ju Hee;Puviindran, Vijitha;Tam, Davis;Shen, Michael;Son, Joe Eun;Vakili, Niki Alizadeh;Sung, Hoon-Ki;Naranjo, Silvia;Acemel, Rafael D.;Manzanares, Miguel;Nagy, Andras;Cox, Nancy J.;Hui, Chi-Chung;Luis Gomez-Skarmeta, Jose;Nobrega, Marcelo A.
通讯作者：
Nobrega, Marcelo A.