Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome
Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome
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DOI：
10.1681/asn.2018070759
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发表时间：
2018-12-01
影响因子：
13.6
通讯作者：
Smith, Richard J. H.
中科院分区：
文献类型：
--
作者：
Bu, Fengxiao;Zhang, Yuzhou;Smith, Richard J. H.
背景非典型溶血性尿毒症综合征(AHUS)是一种危及生命的血栓性微血管病，补体基因的遗传变异是一种易感因素，但对其影响的解释具有挑战性且常常含糊不清。方法我们分析了400例aHUS患者的93个补体和凝血基因，并以来自爱荷华州的600名健康人和63345名非芬兰欧洲人作为对照。在调整了群体分层后，我们应用Fisher精确检验、改进的Poisson精确检验和最优统一序列核关联检验来评估基于基因的变异负担。结果我们发现aHUS患者在CFH、C3、CD46、CFI、DGKE和VTN基因上存在超长编码变异。大部分意义是由微小等位基因频率为0.1%的变异造成的，除非有有效的浓缩和/或功能证据，否则不应被认为是致病的。VTN编码维生素C蛋白，是补体末端途径的一种抑制因子，被认为是一个新的aHUS相关基因。AHUS患者的补体基因中没有多种罕见的变异。总的来说，这些数据可能有助于指导aHUS的临床治疗。
Background Genetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous.Methods We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggregation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant.Results We found that patients with aHUS are enriched for ultrarare coding variants in the CFH, C3, CD46, CFI, DGKE, and VTN genes. The majority of the significance is contributed by variants with a minor allele frequency of 0.1% should not be considered pathogenic unless valid enrichment and/or functional evidence are available. VTN, which encodes vitronectin, an inhibitor of the terminal complement pathway, is implicated as a novel aHUS-associated gene. Patients with aHUS are not enriched for multiple rare variants in complement genes. In aggregate, these data may help in directing clinical management of aHUS.