An Asian-specific MPL genetic variant alters JAK-STAT signaling and influences platelet count in the population
Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population...
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| Veröffentlicht in: | Human molecular genetics Jg. 30; H. 9; S. 836 |
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28.05.2021
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| Abstract | Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count. |
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| AbstractList | Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count. Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count. |
| Author | Tang, Clara S Sham, Pak Chung Lam, Karen S L Ganesh, Santhi K Zhang, He Gao, Wei Fu, Yi Jia, Jia Zhou, Wei Dong, Yujun Chen, Y Eugene Yu, Haiyi Cheung, Chloe Y Y Yang, Min-Lee Huo, Yong Tse, Hung-Fat Xu, Ming Zhang, Yan Sun, Pengfei Willer, Cristen J |
| Author_xml | – sequence: 1 givenname: Pengfei surname: Sun fullname: Sun, Pengfei organization: Department of Cardiology, Peking University First Hospital, Beijing 100034, China – sequence: 2 givenname: Wei surname: Zhou fullname: Zhou, Wei organization: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA – sequence: 3 givenname: Yi surname: Fu fullname: Fu, Yi organization: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China – sequence: 4 givenname: Chloe Y Y surname: Cheung fullname: Cheung, Chloe Y Y organization: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China – sequence: 5 givenname: Yujun surname: Dong fullname: Dong, Yujun organization: Department of Hematology, Peking University First Hospital, Beijing 100034, China – sequence: 6 givenname: Min-Lee surname: Yang fullname: Yang, Min-Lee organization: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA – sequence: 7 givenname: He surname: Zhang fullname: Zhang, He organization: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA – sequence: 8 givenname: Jia surname: Jia fullname: Jia, Jia organization: Department of Cardiology, Peking University First Hospital, Beijing 100034, China – sequence: 9 givenname: Yong surname: Huo fullname: Huo, Yong organization: Department of Cardiology, Peking University First Hospital, Beijing 100034, China – sequence: 10 givenname: Cristen J surname: Willer fullname: Willer, Cristen J organization: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA – sequence: 11 givenname: Y Eugene surname: Chen fullname: Chen, Y Eugene organization: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA – sequence: 12 givenname: Clara S surname: Tang fullname: Tang, Clara S organization: Department of Surgery, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China – sequence: 13 givenname: Hung-Fat surname: Tse fullname: Tse, Hung-Fat organization: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China – sequence: 14 givenname: Karen S L surname: Lam fullname: Lam, Karen S L organization: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China – sequence: 15 givenname: Wei surname: Gao fullname: Gao, Wei organization: Department of Cardiology, Peking University Third Hospital, Beijing 100083, China – sequence: 16 givenname: Ming surname: Xu fullname: Xu, Ming organization: Department of Cardiology, Peking University Third Hospital, Beijing 100083, China – sequence: 17 givenname: Haiyi surname: Yu fullname: Yu, Haiyi organization: Department of Cardiology, Peking University Third Hospital, Beijing 100083, China – sequence: 18 givenname: Pak Chung surname: Sham fullname: Sham, Pak Chung organization: Department of Psychiatry and Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China – sequence: 19 givenname: Yan orcidid: 0000-0002-7508-4160 surname: Zhang fullname: Zhang, Yan organization: Institute of Cardiovascular Disease?Peking University First Hospital, Beijing, 100034, China – sequence: 20 givenname: Santhi K surname: Ganesh fullname: Ganesh, Santhi K organization: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA |
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| Title | An Asian-specific MPL genetic variant alters JAK-STAT signaling and influences platelet count in the population |
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