Genetic interaction of DGAT2 and FAAH in the development of human obesity
Genetic interaction of DGAT2 and FAAH in the development of human obesity
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DGAT2 和 FAAH 在人类肥胖发展中的遗传相互作用。
DOI：
10.1007/s12020-017-1261-1
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发表时间：
2017-05-01
期刊：
影响因子：
3.7
通讯作者：
Ning, Guang
中科院分区：
文献类型：
--
作者：
Ning, Tinglu;Zou, Yaoyu;Ning, Guang
目的DGAT 2是甘油三酯生物合成的关键催化酶，甘油三酯在脂肪组织中的过量积累是肥胖的一个基本过程。迄今为止，尚未报道人类中与肥胖相关的DGAT 2或其他与DGAT 2相互作用的基因突变。方法根据我们的家庭数据库-外显子组测序227名年轻肥胖受试者，鉴定DGAT 2突变（体重指数（BMI），35.1-61.7 kg/m2）和219名瘦对照（BMI，17.5-23.0 kg/m2），在1190名瘦受试者和先证者的家系中进一步验证。先证者的三个基因组进一步进行全外显子测序，以探索肥胖的候选基因。结果我们检测到DGAT 2基因的两种罕见突变，在肥胖和消瘦个体之间没有显著差异。在1名肥胖受试者中发现了一种新的杂合无义变异c.382C > T（p.R128*），但在219名瘦受试者和另外1190名瘦受试者中没有发现。值得注意的是，体外研究表明，R128* 突变严重损害DGAT 2的TG-生物合成能力，并且该家系中的所有其他R128* 携带者都是瘦的。因此，我们进一步鉴定了功能丧失变体c。遗传自肥胖父亲的先证者FAAH中944 G> T（p.R315I）。重要的是，FAAH过表达抑制DGAT 2的表达和TG合成，而R315 I突变体在很大程度上消除了这种抑制作用。结论我们首次报告的功能缺失突变DGAT 2和FAAH在一个肥胖的主题，这可能会相互作用，影响肥胖症的发病率，提供了一个与人类肥胖相关的遗传相互作用的模型。
Purpose DGAT2 is the critical catalyzing enzyme for triglyceride biosynthesis, and excess triglyceride accumulation in fat tissues is a fundamental process for obesity. Mutations in DGAT2 or other genes interacting with DGAT2 associated with adiposity have not been reported in human to date.Methods DGAT2 mutation was identified based on our in-home database-exome sequencing 227 young obese subjects (body-mass index (BMI), 35.1-61.7 kg/m(2)) and 219 lean controls (BMI, 17.5-23.0 kg/m(2)), further validated in 1190 lean subjects and the pedigree of the proband. The trios of the proband were further subjected to whole-exome sequencing to explore the candidate genes for obesity. The mutations in DGAT2 and FAAH were functionally evaluated in vitro.Results We detected two rare variants in DGAT2 with no significant difference between obese and lean individuals. One novel heterozygous nonsense variant c.382C > T (p.R128*) was identified in one obese subject but not in 219 lean subjects and another 1190 lean subjects. Notably, in vitro study showed that R128* mutation severely damaged the TG-biosynthesis ability of DGAT2, and all other R128* carriers in the pedigree were lean. Thus, we further identified a loss-of-function variant c. 944G > T (p.R315I) in FAAH in the proband inheriting from his obese father. Importantly, FAAH overexpression inhibited DGAT2 expression and TG synthesis, while R315I mutant largely eliminated this inhibitory effect.Conclusion We first report loss-of-function mutations in DGAT2 and FAAH in one obese subject, which may interact with each other to affect the adiposity penetrance, providing a model of genetic interaction associated with human obesity.