Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
The Center for Applied Genomics, Children's Hospital of Philadelphia, Research Institute, Leonard Madlyn Abramson Research Center, Suite 1216E, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.
Sci Rep. 2024 Aug 29;14(1):20070. doi: 10.1038/s41598-024-70922-5.
Sickle cell disease (SCD) is an inherited blood disorder marked by homozygosity of hemoglobin S, which is a defective hemoglobin caused by a missense mutation in the β-globin gene. However, clinical phenotypes of SCD vary among patients. To investigate genetic variants associated with various clinical phenotypes of SCD, we genotyped DNA samples from 520 SCD subjects and used a genome-wide association study (GWAS) approach to identify genetic variants associated with phenotypic features of SCD. For HbF levels, the previously reported 2p16.1 locus (BCL11A) reached genome significance (rs1427407, P = 8.58 × 10) in our GWAS as expected. In addition, we found a new genome-wide significance locus at 15q14 (rs8182015, P = 2.07 × 10) near gene EMC7. GWAS of acute chest syndrome (ACS) detected a locus (rs79915189, P = 3.70 × 10) near gene IDH2 at 15q26.1. The SNP, rs79915189, is also an expression quantitative trait locus (eQTL) of IDH2 in multiple tissues. For vasoocclusive episode (VOE), GWAS detected multiple significant signals at 2p25.1 (rs62118798, P = 4.27 × 10), 15q26.1 (rs62020555, P = 2.04 × 10) and 15q26.3 (rs117797325, P = 4.63 × 10). Our findings provide novel insights into the genetic mechanisms of SCD suggesting that common genetic variants play an important role in the presentation of the clinical phenotypes of patients with SCD.
镰状细胞病（SCD）是一种遗传性血液疾病，其特征为血红蛋白 S 纯合子，血红蛋白 S 是由于β-珠蛋白基因的错义突变而导致的缺陷血红蛋白。然而，SCD 患者的临床表型存在差异。为了研究与 SCD 各种临床表型相关的遗传变异，我们对 520 名 SCD 患者的 DNA 样本进行了基因分型，并使用全基因组关联研究（GWAS）方法来鉴定与 SCD 表型特征相关的遗传变异。对于 HbF 水平，我们的 GWAS 如预期的那样，在先前报道的 2p16.1 位点（BCL11A）（rs1427407，P=8.58×10）达到了全基因组显著水平。此外，我们在 15q14 附近发现了一个新的全基因组显著位点（rs8182015，P=2.07×10），该位点靠近 EMC7 基因。急性胸部综合征（ACS）的 GWAS 检测到 15q26.1 附近基因 IDH2 处的一个位点（rs79915189，P=3.70×10）。SNP rs79915189 也是多个组织中 IDH2 的表达数量性状基因座（eQTL）。对于血管阻塞性发作（VOE），GWAS 在 2p25.1（rs62118798，P=4.27×10）、15q26.1（rs62020555，P=2.04×10）和 15q26.3（rs117797325，P=4.63×10）处检测到多个显著信号。我们的研究结果为 SCD 的遗传机制提供了新的见解，表明常见的遗传变异在 SCD 患者临床表型的表现中发挥着重要作用。
