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 follow up on 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 3 GPR151 putative loss-of-function (plof) variants (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7) with a cumulative allele frequency of 2.2% and present at homozygosity. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits. GPR151 deficiency in complete human knockouts is not associated with a clinically significant difference in BMI. Moreover, loss of GPR151 confers a nominally significant increase in risk of T2D (odds ratio = 1.2, p value = 0.03). Relative to wild-type mice, Gpr151^-/- animals exhibit no difference in body weight on normal chow, and higher body weight on a high-fat diet, consistent with the findings in humans. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach for obesity.

中文翻译：

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分析人类基因敲除以验证 GPR151 作为降低体重指数的治疗靶点

需要新的药物靶点来持续降低体重指数 (BMI)，以遏制肥胖的流行，肥胖影响着全球 6.5 亿人，是心血管和代谢疾病及死亡率的一个因果驱动因素。先前的研究报告称，GPR151 的 Arg95Ter 无义变体（一种孤儿 G 蛋白偶联受体）与 BMI 降低和 2 型糖尿病 (T2D) 风险降低有关。在这里，我们跟进GPR151巴基斯坦基因组资源 (PGR) 是世界上最大的人类纯合功能丧失携带者（基因敲除）外显子组生物库之一。在 PGR 参与者中，我们确定了 3 个 GPR151 假定的功能丧失 (plof) 变体（Arg95Ter、Tyr99Ter 和 Phe175LeufsTer7），其累积等位基因频率为 2.2%，并以纯合性存在。我们在体外确认这些等位基因是功能丧失。我们测试GPR151 plof 是否与 BMI、T2D 或其他代谢特征相关。完全人类基因敲除中GPR151 的缺乏与 BMI 的临床显着差异无关。此外，GPR151 的丢失T2D 风险名义上显着增加（优势比 = 1.2，p 值 = 0.03）。相对于野生型小鼠，Gpr151 ^-/-动物在正常食物下的体重没有差异，而在高脂肪饮食下的体重则更高，这与人类的发现一致。总之，我们的研究结果表明 GPR151 拮抗剂不是一种引人注目的肥胖治疗方法。