Genetics of obesity.
Genetics of obesity.
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DOI：
10.2165/00129785-200202030-00003
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发表时间：
2002-01-01
期刊：
影响因子：
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通讯作者：
Froguel, Philippe
中科院分区：
文献类型：
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作者：
Clement, Karine;Boutin, Philippe;Froguel, Philippe
肥胖是一种典型的多因素疾病，其中环境和遗传因素相互作用。在罕见的儿童期发病的严重肥胖症病例中，单个基因在决定肥胖症的发生方面具有主要作用，而环境在表型的严重程度方面仅起允许作用。瘦素基因及其受体、阿黑皮素原（POMC）、激素原转化酶1（PC 1）的异常突变以及更常见的黑皮素受体4（1 - 4%的非常肥胖病例）突变已被描述。所有这些肥胖基因编码的蛋白质作为调节食物摄入的同一环的一部分紧密相连。它们都涉及瘦素轴及其下丘脑靶点之一：黑皮质素通路。单基因型肥胖中涉及的体重调节途径可能是未来药物开发的目标。在瘦素缺乏儿童中成功的瘦素蛋白替代有助于验证人类基因筛查的有用性。然而，瘦素治疗的个体差异可能与遗传变异有关。瘦素本身或瘦素受体的小分子激动剂的效率应与瘦素基因启动子中的遗传变异相关进行研究。最常见的肥胖形式是多基因的。迄今为止，在寻找人类常见多基因肥胖症的基因方面已使用了两种通用方法。第一种方法侧重于选定的基因有一些合理的作用，在肥胖的基础上，他们已知的或假定的生物学作用。这种方法产生了假定的易感基因，只有很小或不确定的影响。第二种方法试图纯粹通过位置来绘制基因图谱，并且不需要对基因的功能进行任何假设。全基因组扫描确定染色体区域显示与肥胖的核心家庭的大集合。不同种族人群的全基因组扫描将主要肥胖基因定位在染色体2、5、10、11和20上。肥胖易感基因可以在连锁区间进行定位克隆。本文对候选基因和主要肥胖连锁区定位克隆方法进行了讨论。
Obesity is a typical common multifactorial disease in which environmental and genetic factors interact. In rare cases of severe obesity with childhood onset, a single gene has a major effect in determining the occurrence of obesity, with the environment having only a permissive role in the severity of the phenotype. Exceptional mutations of the leptin gene and its receptor, pro-opiomelanocortine (POMC), prohormone convertase 1 (PC1) and more frequently, mutations in the melanocortin receptor 4 (1 to 4% of very obese cases) have been described. All these obesity genes encode proteins that are strongly connected as part of the same loop of the regulation of food intake. They all involve the leptin axis and one of its hypothalamic targets; the melanocortin pathway. Pathways of bodyweight regulation involved in monogenic forms of obesity might represent targets for future drug development. Successful leptin protein replacement in a leptin-deficient child has contributed to the validation of the usefulness of gene screening in humans. However, the individual variability in response to leptin treatment might be related to genetic variability. The efficiency of leptin itself or of small-molecule agonists of the leptin receptor should be studied in relation with genetic variations in the leptin gene promoter. The most common forms of obesity are polygenic. Two general approaches have been used to date in the search for genes underlying common polygenic obesity in humans. The first approach focuses on selected genes having some plausible role in obesity on the basis of their known or presumed biological role. This approach yielded putative susceptibility genes with only small or uncertain effects. The second approach attempts to map genes purely by position and requires no presumptions on the function of genes. Genome-wide scans identify chromosomal regions showing linkage with obesity in large collections of nuclear families. Genome-wide scans in different ethnic populations have localized major obesity loci on chromosomes 2, 5, 10, 11 and 20. Susceptibility gene(s) for obesity may be positionally cloned in the intervals of linkage. The candidate gene and positional cloning of major obesity-linked regions approaches are discussed in this paper.