Association of 7q22..1 gene VGF with obesity & leanness

描述（由申请人提供）：复杂的神经回路和大量的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，该多肽以组织特异性的方式进行差异切割，并由内分泌、神经内分泌和神经元细胞分泌。我们已经表明，VGF的靶向删除导致摄食和能量平衡调节的深刻改变；VGF突变小鼠瘦，多动，高代谢和高度抵抗肥胖和糖尿病。有趣的是，许多独立的遗传连锁研究一致表明，在7q22.1的VGF位点上有一个与肥胖相关的亚区，但致病基因尚未确定。基于其在独立研究中的一致性联系和强大的生物学候选性，我们假设VGF是人类肥胖和瘦的优秀候选基因，并建议使用临床和基础科学相结合的方法来研究这一点。我们中的一个（JAM）将在魁北克家庭研究（QFS）患者队列中使用高密度单核苷酸多态性（SNPs）面板进行遗传关联研究，该队列代表了来自950个个体和223个家庭的良好特征样本。几个非同义的、改变蛋白质的snp已经被发现，VGF位点上的其他snp将被开发出来，并被充分表征为潜在的功能变体和/或生物标志物。这些单核苷酸多态性和单倍型将在另一个1425人的独立队列中进行验证。同步生物学研究（SRJS）将使用基因敲除和敲入策略，在小鼠模型中研究选择的人类VGF snp的功能，并在各种体外细胞培养模型中研究VGF的表达、加工和调节释放。由于靶向VGF缺失产生的小鼠更瘦，并且对饮食诱导和某些形式的遗传诱导肥胖具有抗性，因此来自这些小鼠的组织，包括脂肪和肌肉，将通过高密度基因表达阵列分析用于识别其他基因产物。这些生理上相关的靶组织基因本身可能在肥胖抵抗或易感性中发挥功能作用，因此成为未来研究的优秀候选者。

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.