PDF(Pubmed)
Abstract：
The aim of this study was to identify genetic markers in the HBB Cluster; HBS1L-MYB intergenic region; and BCL11A, KLF1, FOX3, and ZBTB7A genes associated with the heterogeneous phenotypes of Sickle Cell Anemia (SCA) using next-generation sequencing, as well as to assess their influence and prevalence in an Angolan population. Hematological, biochemical, and clinical data were considered to determine patients\' severity phenotypes. Samples from 192 patients were sequenced, and 5,019,378 variants of high quality were registered. A catalog of candidate modifier genes that clustered in pathophysiological pathways important for SCA was generated, and candidate genes associated with increasing vaso-occlusive crises (VOC) and with lower fetal hemoglobin (HbF) were identified. These data support the polygenic view of the genetic architecture of SCA phenotypic variability. Two single nucleotide polymorphisms in the intronic region of 2q16.1, harboring the BCL11A gene, are genome-wide and significantly associated with decreasing HbF. A set of variants was identified to nominally be associated with increasing VOC and are potential genetic modifiers harboring phenotypic variation among patients. To the best of our knowledge, this is the first investigation of clinical variation in SCA in Angola using a well-customized and targeted sequencing approach.
摘要：
这项研究的目的是鉴定HBB簇的遗传标记;HBS1L-MYB基因间区域;和BCL11A,KLF1，FOX3和ZBTB7A基因与镰状细胞贫血（SCA）的异质性表型相关，使用下一代测序，以及评估它们在安哥拉人口中的影响和患病率。血液学,生物化学，和临床数据被认为是确定患者的严重程度表型。对192名患者的样本进行了测序，并注册了5,019,378种高质量的变体。产生了聚集在对SCA重要的病理生理途径中的候选修饰基因的目录，并确定了与血管闭塞危象（VOC）增加和胎儿血红蛋白（HbF）降低相关的候选基因。这些数据支持SCA表型变异性遗传结构的多基因观点。2q16.1内含子区的两个单核苷酸多态性，带有BCL11A基因，是全基因组的，并且与HbF降低显着相关。一组变体被鉴定为名义上与增加的VOC相关,并且是在患者中具有表型变异的潜在遗传修饰物。据我们所知,这是首次使用定制和靶向测序方法对安哥拉的SCA临床变异进行调查.
