Grant Struan F A, Hakonarson Hakon
Center for Applied Genomics, The Children's Hospital of Philadelphia, PA 19104-4318, USA.
Expert Rev Mol Diagn. 2007 Jul;7(4):371-93. doi: 10.1586/14737159.7.4.371.
Genetic diversity, most notably through single nucleotide polymorphisms and copy-number variation, together with specific environmental exposures, contributes to both disease susceptibility and drug response variability. It has proved difficult to isolate disease genes that confer susceptibility to complex disorders, and as a consequence, even fewer genetic variants that influence clinical drug responsiveness have been uncovered. As such, the candidate gene approach has largely failed to deliver and, although the family-based linkage approach has certain theoretical advantages in dealing with common/complex disorders, progress has been slower than was hoped. More recently, genome-wide association studies have gained increasing popularity, as they enable scientists to robustly associate specific variants with the predisposition for complex disease, such as age-related macular degeneration, Type 2 diabetes, inflammatory bowel disease, obesity, autism and leukemia. This relatively new methodology has stirred new hope for the mapping of genes that regulate drug response related to these conditions. Collectively, these studies support the notion that modern high-throughput single nucleotide polymorphism genotyping technologies, when applied to large and comprehensively phenotyped patient cohorts, will readily reveal the most clinically relevant disease-modifying and drug response genes. This review addresses both recent advances in the genotyping field and highlights from genome-wide association studies, which have conclusively uncovered variants that underlie disease susceptibility and/or variability in drug response in common disorders.
遗传多样性，尤其是通过单核苷酸多态性和拷贝数变异，以及特定的环境暴露，导致了疾病易感性和药物反应变异性。事实证明，分离出导致复杂疾病易感性的疾病基因很困难，因此，发现影响临床药物反应性的基因变异就更少了。因此，候选基因方法在很大程度上未能取得成效，尽管基于家系的连锁分析方法在处理常见/复杂疾病方面具有一定的理论优势，但进展比预期的要慢。最近，全基因组关联研究越来越受欢迎，因为它们使科学家能够有力地将特定变异与复杂疾病的易感性联系起来，如年龄相关性黄斑变性、2型糖尿病、炎症性肠病、肥胖症、自闭症和白血病。这种相对较新的方法为绘制与这些疾病相关的药物反应调控基因带来了新的希望。总的来说，这些研究支持这样一种观点，即现代高通量单核苷酸多态性基因分型技术应用于大规模且具有全面表型的患者队列时，将很容易揭示出最具临床相关性的疾病修饰基因和药物反应基因。这篇综述既阐述了基因分型领域的最新进展，也强调了全基因组关联研究的成果，这些研究已经明确发现了常见疾病中疾病易感性和/或药物反应变异性的潜在变异。
