Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv 69978, Israel.
Nat Rev Nephrol. 2011 Jun;7(6):313-26. doi: 10.1038/nrneph.2011.52. Epub 2011 May 3.
Many rare kidney disorders exhibit a monogenic, Mendelian pattern of inheritance. Population-based genetic studies have identified many genetic variants associated with an increased risk of developing common kidney diseases. Strongly associated variants have potential clinical uses as predictive markers and may advance our understanding of disease pathogenesis. These principles are elegantly illustrated by a region within chromosome 22q12 that has a strong association with common forms of kidney disease. Researchers had identified DNA sequence variants in this locus that were highly associated with an increased prevalence of common chronic kidney diseases in people of African ancestry. Initial research concentrated on MYH9 as the most likely candidate gene; however, population-based whole-genome analysis enabled two independent research teams to discover more strongly associated mutations in the neighboring APOL1 gene. The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease. We describe the data sources, process of discovery, and reasons for initial misidentification of the candidate gene, as well as the lessons that can be learned for future population genetics research.
许多罕见的肾脏疾病表现出单基因、孟德尔遗传模式。基于人群的遗传研究已经确定了许多与常见肾脏疾病风险增加相关的遗传变异。与疾病发病机制相关的强关联变异具有作为预测标志物的潜在临床用途，并可能促进我们对疾病发病机制的理解。这些原则在染色体 22q12 内的一个区域得到了很好的体现，该区域与常见的肾脏疾病形式有很强的关联。研究人员在该基因座中发现了与非洲裔人群中常见慢性肾脏疾病患病率增加高度相关的 DNA 序列变异。最初的研究集中在 MYH9 作为最有可能的候选基因上；然而，基于人群的全基因组分析使两个独立的研究小组能够在邻近的 APOL1 基因中发现与更强烈相关的突变。在西非，一种传染性病原体的强大进化选择压力有利于 APOL1 变异的传播，这些变异可以预防致命的非洲昏睡病，但与肾脏疾病风险增加高度相关。我们描述了数据来源、发现过程以及候选基因最初被错误识别的原因，以及可以为未来的群体遗传学研究吸取的教训。
