Bastarrachea Raúl A, Cole Shelley A, Comuzzie Anthony G
Department of Genetics, Auxology and Metabolism Working Group, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA.
Med Clin (Barc). 2004 Jun 19;123(3):104-17. doi: 10.1016/s0025-7753(04)74427-9.
Obesity has become a worldwide public health problem which affects millions of people. Substantial progress has been made in elucidating the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Twin, adoption and family studies have shown that genetic factors play a significant role in the pathogenesis of obesity. Human monogenic obesity is rare in large populations. The most common form of obesity is considered to be a polygenic disorder. New treatments are currently required for this common metabolic disease and type 2 diabetes. The identification of physiological and biochemical factors that underlie the metabolic disturbances observed in obesity is a key step in developing better therapeutic outcomes. The discovery of new genes and pathways involved in the pathogenesis of such a disease is critical to this process. However, identification of genes that contribute to the risk of developing the disease represents a significant challenge since obesity is a complex disease with many genetic and environmental causes. A number of diverse approaches have been used to discover and validate potential new genes for obesity. To date, DNA-based approaches using candidate genes and genome-wide linkage analysis have not had a great success in identifying genomic regions or genes involved in the development of these diseases. Recent advances in the ability to evaluate linkage analysis data from large family pedigrees (using variance components-based linkage analysis) show great promise in robustly identifying genomic regions associated with the development of obesity. Studying rare mutations in humans and animal models has provided fundamental insight into a complex physiological process, and has complemented population-based studies that seek to reveal primary causes. Remarkable progress has been made in both fronts and the pace of advance is likely to accelerate as functional genomics and the human genome project expand and mature. Approaches based on Mendelian and quantitative genetics may well converge, and ultimately lead to more rational and selective therapies.
肥胖已成为一个影响数百万人的全球性公共卫生问题。在过去几年中，我们在阐明能量稳态的发病机制方面取得了重大进展。肥胖受到强大的基因控制这一事实已得到充分证实。双胞胎、收养和家族研究表明，遗传因素在肥胖的发病机制中起着重要作用。人类单基因肥胖在大群体中较为罕见。最常见的肥胖形式被认为是一种多基因疾病。目前，这种常见的代谢疾病和2型糖尿病需要新的治疗方法。确定肥胖中观察到的代谢紊乱背后的生理和生化因素是取得更好治疗效果的关键一步。发现参与此类疾病发病机制的新基因和途径对这一过程至关重要。然而，由于肥胖是一种由多种遗传和环境原因导致的复杂疾病，确定导致该疾病发病风险的基因是一项重大挑战。人们已采用多种不同方法来发现和验证肥胖潜在的新基因。迄今为止，使用候选基因和全基因组连锁分析的基于DNA的方法在识别参与这些疾病发展的基因组区域或基因方面并未取得巨大成功。评估大型家系连锁分析数据（使用基于方差成分的连锁分析）能力的最新进展在可靠识别与肥胖发展相关的基因组区域方面显示出巨大潜力。研究人类和动物模型中的罕见突变，为深入了解复杂的生理过程提供了基本见解，并补充了旨在揭示主要病因的基于人群的研究。在这两方面都取得了显著进展，随着功能基因组学和人类基因组计划的扩展与成熟，进展速度可能会加快。基于孟德尔遗传学和数量遗传学的方法很可能会融合，并最终导致更合理、更具选择性的治疗方法。
