Bougnères Pierre
Service d'Endocrinologie, Unité 561 INSERM, Hôpital Saint Vincent de Paul, Paris, France.
Diabetes. 2002 Dec;51 Suppl 3:S295-303. doi: 10.2337/diabetes.51.2007.s295.
The modern generalization of sedentary life and caloric abundance has created new physiological conditions capable of changing the level of expression of a number of genes involved in fuel metabolism and body weight regulation. It is likely that the genetic variants or alleles of these genes have in the past participated in the adaptation of human physiology to its evolutionary constraints. The nature and prevalence of polymorphisms responsible for the quantitative variation of complex metabolic traits may have been different among human populations, depending on their environment and ancestral genetic background. These polymorphisms could likely explain differences in disease susceptibility and prevalence among groups of humans. From complex traits to potentially complex alleles, understanding the molecular genetic basis underlying quantitative variation will continue to be a growing concern among geneticists dealing with obesity and type 2 diabetes, the main fuel disorders of the modern era. Genomics and genetic epidemiology now allow high-level linkage and association studies to be designed. But the pooling of large trans-geographic cohorts may in fact increase the genetic heterogeneity of studied traits and dilute genotype-phenotype associations. In this article, we underscore the importance of selecting the traits to be subjected to quantitative genetic analysis. Although this is not possible for most other multifactorial diseases, obesity and type 2 diabetes can be subjected to a pregenetic dissection of complexity into simpler quantitative traits (QTs). This dissection is based on the pathogenic mechanisms, and the time course of the traits, and the individuals' age, within the predisease period rather than on descriptive parameters after disease diagnosis. We defend that this approach of phenotypes may ease future associations to be established between QTs of intermediate complexity and genetic polymorphisms.
现代久坐不动的生活方式和热量过剩的普遍现象创造了新的生理条件，能够改变许多参与燃料代谢和体重调节的基因的表达水平。这些基因的遗传变异或等位基因过去可能参与了人类生理对其进化限制的适应过程。负责复杂代谢性状数量变异的多态性的性质和流行程度在不同人群中可能有所不同，这取决于他们的环境和祖先遗传背景。这些多态性可能解释了人类群体之间疾病易感性和患病率的差异。从复杂性状到潜在的复杂等位基因，了解数量变异背后的分子遗传基础将继续是处理肥胖症和2型糖尿病（现代主要的燃料紊乱疾病）的遗传学家日益关注的问题。基因组学和遗传流行病学现在允许设计高水平的连锁和关联研究。但是，汇集大型跨地理队列实际上可能会增加所研究性状的遗传异质性，并稀释基因型与表型之间的关联。在本文中，我们强调选择要进行数量遗传分析的性状的重要性。虽然对于大多数其他多因素疾病来说这是不可能的，但肥胖症和2型糖尿病可以在疾病前期基于致病机制、性状的时间进程以及个体年龄，将复杂性进行遗传前剖析，分解为更简单的数量性状（QTs），而不是基于疾病诊断后的描述性参数。我们认为这种表型分析方法可能会便于在中等复杂性的数量性状与遗传多态性之间建立未来的关联。
