Hoehe Margret R, Kroslak Thomas
Genetic Variation Program, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Dialogues Clin Neurosci. 2004 Mar;6(1):5-26. doi: 10.31887/DCNS.2004.6.1/mhoehe.
The analysis of genetic variation in candidate genes is an issue of central importance in pharmacogenomics. The specific approaches taken will have a critical impact on the successful identification of disease genes, the molecular correlates of drug response, and the establishment of meaningful relationships between genetic variants and phenotypes of biomedical and pharmaceutical importance in general. Against a historical background, this article distinguishes different approaches to candidate gene analysis, reflecting different stages in human genome research. Only recently has it become feasible to analyze genetic variation systematically at the ultimate level of resolution, ie, the DNA sequence. In this context, the importance of haplotype-based approaches to candidate gene analysis has at last been recognized; the determination of the specific combinations of variants for each of the two sequences of a gene defined as a haplotype is essential. An up-to-date summary of such maximum resolution data on the amount, nature, and structure of genetic variation in candidate genes will be given. These data demonstrate abundant gene sequence and haplotype diversity. Numerous individually different forms of a gene may exist. This presents major challenges to the analysis of relationships between genetic variation, gene function, and phenotype. First solutions seem within reach. The implications of naturally occurring variation for pharmacogenomics and "personalized" medicine are now evident. Future approaches to the identification, evaluation, and prioritization of drug targets, the optimization of clinical trials, and the development of efficient therapies must be based on in-depth knowledge of candidate gene variation as an essential prerequisite.
候选基因的遗传变异分析是药物基因组学的核心重要问题。所采用的具体方法将对疾病基因的成功鉴定、药物反应的分子关联以及一般而言在生物医学和制药领域具有重要意义的遗传变异与表型之间有意义关系的建立产生关键影响。基于历史背景，本文区分了候选基因分析的不同方法，反映了人类基因组研究的不同阶段。直到最近，在最终分辨率水平（即DNA序列）上系统分析遗传变异才变得可行。在这种背景下，基于单倍型的候选基因分析方法的重要性终于得到认可；确定定义为单倍型的基因的两条序列中每条序列的变异体的特定组合至关重要。将给出关于候选基因遗传变异的数量、性质和结构的此类最高分辨率数据的最新总结。这些数据表明存在丰富的基因序列和单倍型多样性。一个基因可能存在许多个体不同的形式。这给遗传变异、基因功能和表型之间关系的分析带来了重大挑战。首批解决方案似乎已近在咫尺。自然发生的变异对药物基因组学和“个性化”医学的影响现在已经很明显。未来识别、评估和确定药物靶点优先级、优化临床试验以及开发有效疗法的方法必须基于对候选基因变异的深入了解，这是一个必不可少的先决条件。
