Genes in human obesity loci are causal obesity genes in C. elegans.
Genes in human obesity loci are causal obesity genes in C. elegans.
复制标题
人类肥胖基因座中的基因是C.优雅的
DOI：
10.1371/journal.pgen.1009736
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发表时间：
2021-09
期刊：
影响因子：
4.5
通讯作者：
O'Rourke EJ
中科院分区：
文献类型：
--
作者：
Ke W;Reed JN;Yang C;Higgason N;Rayyan L;Wählby C;Carpenter AE;Civelek M;O'Rourke EJ
肥胖及其相关代谢综合征是发病和死亡的主要原因。鉴于该疾病给患者和医疗保健系统带来沉重负担，人们对确定治疗和预防肥胖的药理学靶点越来越感兴趣。为此，全基因组关联研究（GWAS）已经确定了数百种与肥胖相关的人类遗传变异。下一个挑战是通过实验确定这些变异中哪些与肥胖有因果关系，因此可能成为治疗或预防肥胖的目标。在这里，我们采用高通量体内 RNAi 筛选来测试 GWAS 中报告的人类肥胖候选基因的 293 线虫直系同源物的因果关系。我们通过 RNAi 筛选了接受两种不同喂养方案的线虫中的这 293 个基因：(1) 常规饮食和 (2) 高果糖饮食，我们开发并在此将其作为饮食诱导肥胖 (DIO) 的无脊椎动物模型展示。我们报告了秀丽隐杆线虫中 14 个促进肥胖的基因和 3 个在沉默时预防 DIO 的基因。此外，我们还发现，敲低 3 个 DIO 基因不仅可以防止原代脂肪库和异位脂肪库中的过多脂肪积累，还可以改善过度消耗果糖的线虫的健康状况并延长其寿命。重要的是，这些基因座的表达变异与小鼠和人类肥胖之间的关联方向与线虫直系同源基因功能丧失的表型结果相匹配，支持了其中一些基因与整个系统发育中的肥胖存在因果关系的观点。因此，除了定义迄今为止仅与肥胖相关的几个基因的因果关系之外，本研究还证明了与体内高通量遗传筛选兼容的模型系统的价值，可以将 GWAS 候选基因与人类疾病联系起来。人类 GWAS 已鉴定出数百种与人类肥胖相关的基因变异。在蛋白质或表达水平上受这些变体调节的基因代表了潜在的抗肥胖目标。然而，对于这些基因中的绝大多数，尚不清楚它们是否会导致肥胖或巧合地与该疾病相关。在这里，我们使用高通量遗传筛选策略在秀丽隐杆线虫体内测试人类肥胖 GWAS 命中的潜在因果作用。此外，我们将遗传筛选的结果与小鼠和人类 GWAS 数据库的分析相结合。因此，我们提出了 17 个促进或预防秀丽隐杆线虫肥胖以及与肥胖相关的早期机体退化和死亡的基因。此外，人类基因表达水平与其相关临床特征之间的相关性在很大程度上与在线虫中敲除这些基因的表型效应相匹配，表明这些基因的保守因果关系和药理学潜力。
Obesity and its associated metabolic syndrome are a leading cause of morbidity and mortality. Given the disease’s heavy burden on patients and the healthcare system, there has been increased interest in identifying pharmacological targets for the treatment and prevention of obesity. Towards this end, genome-wide association studies (GWAS) have identified hundreds of human genetic variants associated with obesity. The next challenge is to experimentally define which of these variants are causally linked to obesity, and could therefore become targets for the treatment or prevention of obesity. Here we employ high-throughput in vivo RNAi screening to test for causality 293 C. elegans orthologs of human obesity-candidate genes reported in GWAS. We RNAi screened these 293 genes in C. elegans subject to two different feeding regimens: (1) regular diet, and (2) high-fructose diet, which we developed and present here as an invertebrate model of diet-induced obesity (DIO). We report 14 genes that promote obesity and 3 genes that prevent DIO when silenced in C. elegans. Further, we show that knock-down of the 3 DIO genes not only prevents excessive fat accumulation in primary and ectopic fat depots but also improves the health and extends the lifespan of C. elegans overconsuming fructose. Importantly, the direction of the association between expression variants in these loci and obesity in mice and humans matches the phenotypic outcome of the loss-of-function of the C. elegans ortholog genes, supporting the notion that some of these genes would be causally linked to obesity across phylogeny. Therefore, in addition to defining causality for several genes so far merely correlated with obesity, this study demonstrates the value of model systems compatible with in vivo high-throughput genetic screening to causally link GWAS gene candidates to human diseases. Human GWAS have identified hundreds of genetic variants associated with human obesity. The genes being regulated by these variants at the protein or expression level represent potential anti-obesity targets. However, for the vast majority of these genes, it is unclear whether they cause obesity or are coincidentally associated with the disease. Here we use a high-throughput genetic screening strategy to test in vivo in Caenorhabditis elegans the potential causal role of human-obesity GWAS hits. Further, we combined the results of the genetic screen with analyses of mouse and human GWAS databases. As a result, we present 17 genes that promote or prevent C. elegans obesity, and the early onset of organismal deterioration and death associated with obesity. Further, the sign of the correlation between the expression levels of the human genes and their associated clinical traits matches, for the most part, the phenotypic effects of knocking down these genes in C. elegans, suggesting conserved causality and pharmacological potential for these genes.
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