Lee James C, Biasci Daniele, Roberts Rebecca, Gearry Richard B, Mansfield John C, Ahmad Tariq, Prescott Natalie J, Satsangi Jack, Wilson David C, Jostins Luke, Anderson Carl A, Traherne James A, Lyons Paul A, Parkes Miles, Smith Kenneth G C
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
Department of Medicine, University of Otago, Christchurch, New Zealand.
Nat Genet. 2017 Feb;49(2):262-268. doi: 10.1038/ng.3755. Epub 2017 Jan 9.
For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.
对于大多数免疫介导的疾病，决定患者健康状况的主要因素并非诊断本身，而是疾病随时间发展的进程（预后）。由于了解甚少，患者之间的预后可能有很大差异。家族研究支持遗传因素对预后有影响，但几乎没有证据表明预后与易感性变异负担之间存在所提出的关联。为了更好地描述基因变异如何影响疾病预后，我们在两个克罗恩病患者队列中进行了病例内全基因组关联研究。我们鉴定出四个全基因组显著位点，其中没有一个与疾病易感性相关。相反，所有170个疾病易感性位点的综合效应与疾病预后无关。这些数据共同表明，克罗恩病预后的遗传因素在很大程度上独立于对疾病易感性的影响，并指向一种可能提供新治疗机会的预后生物学。
