Unit of Epidemiology and Population Genetics, Institute of Food Sciences, CNR, Avellino, Italy.
Nutr Metab Cardiovasc Dis. 2010 Dec;20(10):691-7. doi: 10.1016/j.numecd.2010.09.007. Epub 2010 Nov 19.
Obesity is a complex disease, arising from the interaction between several genetic and environmental factors. Until recently, the genetic basis of complex diseases in general, and of obesity in particular, were poorly characterized. While the relatively rare monogenic and syndromic forms of obesity clearly recognize a genetic origin, the actual worldwide epidemics of obesity represent a challenge for the identification of the genetic factors involved, being likely the effect of several loci each having a subtle influence on the phenotypic expression. Progress in DNA analysis techniques and in computational tools, and the increasing level of characterization of the variability of the human genome has recently allowed to study comprehensively the association between genetic variants and obesity. To date, well-conducted and powered genome-wide association studies allowed to consistently identify genomic regions - lying on different chromosomes and affecting different metabolic pathways - influencing the predisposition to the accumulation of body fat, ultimately leading to overweight and obesity. However, the population attributable risk for obesity linked to the most statistically significant loci, like FTO and MC4R, remains discouragingly low, explaining only small fractions of the overall variance of body weight. In the last few years, the role of the complex interaction between genetic determinants and environmental factors in the rapid global increase of obesity has been further challenged by the entry of new players, that is the transcriptional and post-transcriptional regulation, summarized under the emerging discipline of epigenetics. The key challenge now is to move from the identification of causal genes and variants to the integration of different "omics" disciplines, finally allowing the molecular understanding of obesity and related conditions.
肥胖是一种复杂的疾病，源于多种遗传和环境因素的相互作用。直到最近，复杂疾病的遗传基础，尤其是肥胖的遗传基础，都还没有得到很好的描述。虽然相对罕见的单基因和综合征形式的肥胖显然有遗传起源，但实际上肥胖的全球流行是对所涉及遗传因素的识别的一个挑战，可能是由几个对表型表达有细微影响的基因座共同作用的结果。DNA 分析技术和计算工具的进步，以及人类基因组变异特征的不断提高，最近使得我们能够全面研究遗传变异与肥胖之间的关联。迄今为止，精心设计和强大的全基因组关联研究一致地确定了影响体脂肪积累易感性的基因组区域 - 这些区域位于不同的染色体上，并影响不同的代谢途径 - 最终导致超重和肥胖。然而，与最具统计学意义的位点（如 FTO 和 MC4R）相关的肥胖的人群归因风险仍然令人沮丧地低，仅能解释体重总方差的很小一部分。在过去的几年中，遗传决定因素和环境因素之间复杂相互作用在肥胖的全球迅速增加中的作用受到了新参与者的挑战，即转录和转录后调控，这些内容概括在新兴的表观遗传学学科中。现在的关键挑战是将从确定因果基因和变异转移到整合不同的“组学”学科，最终实现对肥胖和相关疾病的分子理解。
