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 qu...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 1020β-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.展开更多
基金supported by research funding from the National Natural Science Foundation of China(Grant No.U20A20353)the Guangdong Basic and Applied Basic Research Foundation(Grant No.2023A1515110850)+1 种基金the China Postdoctoral Science Foundation(Grant No.2023M741585)the Medical Scientific Research Foundation of Guangdong Province(Grant No.A2022443),China.
文摘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 1020β-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.
