GenOmics, Bioinformatics, and Translational Research Center, RTI International, Research Triangle Park, Durham, NC, USA.
Vitalant Research Institute, Denver, CO, USA.
BMC Genomics. 2022 Mar 23;23(1):227. doi: 10.1186/s12864-022-08461-4.
Genetic variants have been found to influence red blood cell (RBC) susceptibility to hemolytic stress and affect transfusion outcomes and the severity of blood diseases. Males have a higher susceptibility to hemolysis than females, but little is known about the genetic mechanism contributing to the difference.
To investigate the sex differences in RBC susceptibility to hemolysis, we conducted a sex-stratified genome-wide association study and a genome-wide gene-by-sex interaction scan in a multi-ethnic dataset with 12,231 blood donors who have in vitro osmotic hemolysis measurements during routine blood storage. The estimated SNP-based heritability for osmotic hemolysis was found to be significantly higher in males than in females (0.46 vs. 0.41). We identified SNPs associated with sex-specific susceptibility to osmotic hemolysis in five loci (SPTA1, KCNA6, SLC4A1, SUMO1P1, and PAX8) that impact RBC function and hemolysis.
Our study established a best practice to identify sex-specific genetic modifiers for sexually dimorphic traits in datasets with mixed ancestries, providing evidence of different genetic regulations of RBC susceptibility to hemolysis between sexes. These and other variants may help explain observed sex differences in the severity of hemolytic diseases, such as sickle cell and malaria, as well as the viability of red cell storage and recovery.
遗传变异已被发现影响红细胞（RBC）对溶血性应激的敏感性，并影响输血结果和血液疾病的严重程度。男性比女性更容易发生溶血，但对于导致这种差异的遗传机制知之甚少。
为了研究 RBC 对溶血的敏感性存在性别差异的原因，我们在一个多民族数据集（该数据集包含 12231 名献血者，他们在常规血液储存期间进行了体外渗透溶血测量）中进行了性别分层的全基因组关联研究和全基因组基因-性别相互作用扫描。结果发现，渗透溶血的 SNP 基于估计的遗传力在男性中明显高于女性（0.46 比 0.41）。我们在五个影响 RBC 功能和溶血的基因座（SPTA1、KCNA6、SLC4A1、SUMO1P1 和 PAX8）中鉴定出与渗透溶血的性别特异性易感性相关的 SNP。
我们的研究建立了一种最佳实践方法，可用于在具有混合祖源的数据集识别性别特异性遗传修饰因子，为男女两性 RBC 对溶血的敏感性的不同遗传调控提供了证据。这些和其他变体可能有助于解释溶血性疾病（如镰状细胞病和疟疾）严重程度的性别差异，以及红细胞储存和恢复的活力。
