Wang Xingmin, Zhang Qianqian, Chen Xianming, Huang Yushan, Zhang Wei, Liao Liuhua, Zhang Xinhua, Huang Binbin, Huang Yueyan, Ye Yuhua, Song Mengyang, Lao Jinquan, Chen Juanjuan, Feng Xiaoqin, Long Xingjiang, Liu Zhixiang, Zhu Weijian, Yu Lian, Fan Chengwu, Tang Deguo, Zhong Tianyu, Fang Mingyan, Li Caiyun, Niu Chao, Huang Li, Lin Bin, Hua Xiaoyun, Jin Xin, Li Zilin, Xu Xiangmin
Innovation Center for Diagnostics and Treatment of Thalassemia, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Genomics Proteomics Bioinformatics. 2025 May 30;23(2). doi: 10.1093/gpbjnl/qzae065.
Platelets act as a crucial indicator for monitoring hypercoagulability and thrombosis and a key target for pharmacological intervention. Genotype-phenotype association studies have confirmed that platelet traits are quantitatively regulated by multiple genes. However, there is currently a lack of genetic studies on the heterogeneity of platelet traits in β-thalassemia under a hypercoagulable state. Here, we studied the phenotypic heterogeneity of platelet count (PLT) and mean platelet volume (MPV) in a cohort of 1020 β-thalassemia patients. We further performed a functionally informed whole-genome sequencing (WGS) association analysis of common variants and rare variants for PLT and MPV in 916 patients through integrative analysis of WGS data and functional annotation data. Extreme phenotypic heterogeneity of platelet traits was observed in β-thalassemia patients. Additionally, the common variant-based gene-level analysis identified RNF144B as a novel gene associated with MPV. The rare variant analysis identified several novel associations in both coding and noncoding regions, including missense rare variants of PPP2R5C associated with PLT and missense rare variants of TSSK1B associated with MPV. In conclusion, this comprehensive and systematic whole-genome scan of platelet traits in the β-thalassemia cohort reveals the specific genetic regulation of platelet traits in the context of β-thalassemia, providing potential targets for intervention.
血小板是监测高凝状态和血栓形成的关键指标，也是药物干预的关键靶点。基因型-表型关联研究已证实血小板特征受多个基因的定量调控。然而，目前缺乏关于β地中海贫血在高凝状态下血小板特征异质性的遗传学研究。在此，我们研究了1020例β地中海贫血患者队列中血小板计数（PLT）和平均血小板体积（MPV）的表型异质性。我们通过对全基因组测序（WGS）数据和功能注释数据的综合分析，进一步对916例患者的PLT和MPV的常见变异和罕见变异进行了功能知情的全基因组测序（WGS）关联分析。在β地中海贫血患者中观察到血小板特征的极端表型异质性。此外，基于常见变异的基因水平分析确定RNF144B是一个与MPV相关的新基因。罕见变异分析在编码区和非编码区均发现了几个新的关联，包括与PLT相关的PPP2R5C错义罕见变异和与MPV相关的TSSK1B错义罕见变异。总之，这项对β地中海贫血队列中血小板特征进行的全面系统的全基因组扫描揭示了β地中海贫血背景下血小板特征的特定遗传调控，为干预提供了潜在靶点。
