Association of 7q22.1 gene VGF with obesity and leaness

描述(申请人提供)：复杂的神经回路和大量的多肽激素和神经肽控制摄食和能量消耗。VGF(非首字母缩写)基因编码一种高度保守的哺乳动物多肽，它以组织特异性的方式被差异切割，并由内分泌、神经内分泌和神经细胞分泌。我们已经证明，定向缺失VGF会导致摄食和能量平衡的调节发生深刻变化；VGF突变小鼠瘦、多动、高代谢，对肥胖和糖尿病具有高度抵抗力。有趣的是，一些独立的遗传连锁研究一直表明，在7q22.1上的VGF基因座上有一个与肥胖有关的亚区的强有力证据，但致病基因尚未确定。基于它在独立研究中的一致连锁和强大的生物学候选能力，我们假设VGF是人类肥胖和瘦的一个极好的候选基因，并建议使用临床和基础科学相结合的方法来研究这一点。我们中的一人(JAM)将使用魁北克家庭研究(QFS)患者队列中的单核苷酸多态(SNPs)高密度小组进行遗传关联研究，该小组代表来自950个个人和223个家庭的特征良好的样本。几个非同义的、改变蛋白质的SNPs已为人所知，将开发更多跨越VGF基因座的SNPs，并将其充分表征为潜在的功能变体和/或生物标记。然后，这些SNP和单倍型区块将在1425名个体的第二个独立队列中得到验证。并发生物学研究(SRJS)将在使用基因敲除和敲入策略的小鼠模型中，以及在可以量化VGF表达、加工和调节释放的各种体外细胞培养模型中，研究精选的人VGF SNPs的功能。由于定向VGF缺失产生的小鼠是瘦小的，对饮食诱导的和某些形式的遗传诱导的肥胖具有抵抗力，这些小鼠的组织，包括脂肪和肌肉，将通过高密度基因表达阵列分析来识别额外的基因产物。这些生理上相关联的靶组织基因本身可能在肥胖抵抗或易感性方面发挥作用，因此成为未来研究的极佳候选者。

DESCRIPTION (provided by applicant): Complex neural circuits and a large number of peptide hormones and neuropeptides control feeding and energy expenditure. The VGF (non-acronymic) gene encodes a highly conserved mammalian polypeptide that is differentially cleaved in a tissue-specific manner and secreted from endocrine, neuroendocrine and neuronal cells. We have shown that targeted deletion of VGF results in profound alterations in the regulation of feeding and energy balance; VGF mutant mice are lean, hyperactive, hypermetabolic and highly resistant to obesity and diabetes. Interestingly, a number of independent genetic linkage studies have consistently shown strong evidence of a subregion linked with obesity over the VGF locus on 7q22.1 but the causative gene has not been identified. Based on its consistent linkage in independent studies and strong biological candidacy, we hypothesize that VGF is an excellent candidate gene for human obesity and leanness, and propose to investigate this using combined clinical and basic science approaches. One of us (JAM) will perform genetic association studies using a high density panel of single nucleotide polymorphisms (SNPs) in the Quebec Family Study (QFS) patient cohort who represents well-characterized samples from 950 individuals and 223 families. Several nonsynonymous, protein-altering SNPs are already known and additional SNPs across the VGF locus will be developed and fully characterized as potential functional variants and/or biomarkers. These SNPs and haplotype blocks will then be validated in a second, independent cohort of 1,425 individuals. Concurrent biologic studies (SRJS) will investigate the function of select human VGF SNPs in mouse models using gene 'knockout' and 'knock-in' strategies, and in various in vitro cell culture models where VGF expression, processing, and regulated release can be quantified. Since targeted VGF deletion generates mice that are lean and resistant to diet-induced and some forms of genetically-induced obesity, tissues from these mice, including adipose and muscle, will be used to identify additional gene products by high-density gene expression array analysis. These physiologically linked, target-tissue genes may themselves play a functional role in obesity resistance or susceptibility, and thus become excellent candidates for future investigation.