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Article: An Asian-specific MPL genetic variant alters JAK–STAT signaling and influences platelet count in the population

TitleAn Asian-specific MPL genetic variant alters JAK–STAT signaling and influences platelet count in the population
Authors
Issue Date2021
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2021, v. 30 n. 9, p. 836-842 How to Cite?
AbstractGenomic 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.
Persistent Identifierhttp://hdl.handle.net/10722/301554
ISSN
2020 Impact Factor: 6.15
2020 SCImago Journal Rankings: 2.811
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorSun, P-
dc.contributor.authorZhou, W-
dc.contributor.authorFu, Y-
dc.contributor.authorCheung, CYY-
dc.contributor.authorDong, Y-
dc.contributor.authorYang, ML-
dc.contributor.authorZhang, H-
dc.contributor.authorJia, J-
dc.contributor.authorHuo, Y-
dc.contributor.authorWiller, CJ-
dc.contributor.authorChen, YE-
dc.contributor.authorTang, CS-
dc.contributor.authorTse, HF-
dc.contributor.authorLam, KSL-
dc.contributor.authorGao, W-
dc.contributor.authorXu, M-
dc.contributor.authorYu, H-
dc.contributor.authorSham, PC-
dc.contributor.authorZhang, Y-
dc.contributor.authorGanesh, SK-
dc.date.accessioned2021-08-09T03:40:46Z-
dc.date.available2021-08-09T03:40:46Z-
dc.date.issued2021-
dc.identifier.citationHuman Molecular Genetics, 2021, v. 30 n. 9, p. 836-842-
dc.identifier.issn0964-6906-
dc.identifier.urihttp://hdl.handle.net/10722/301554-
dc.description.abstractGenomic 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.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/-
dc.relation.ispartofHuman Molecular Genetics-
dc.rightsPost-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here].-
dc.titleAn Asian-specific MPL genetic variant alters JAK–STAT signaling and influences platelet count in the population-
dc.typeArticle-
dc.identifier.emailCheung, CYY: cyy0219@hku.hk-
dc.identifier.emailTang, CS: claratang@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.emailLam, KSL: ksllam@hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.authorityCheung, CYY=rp02243-
dc.identifier.authorityTang, CS=rp02105-
dc.identifier.authorityTse, HF=rp00428-
dc.identifier.authorityLam, KSL=rp00343-
dc.identifier.authoritySham, PC=rp00459-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1093/hmg/ddab062-
dc.identifier.pmid33693786-
dc.identifier.pmcidPMC8161516-
dc.identifier.scopuseid_2-s2.0-85107163710-
dc.identifier.hkuros324153-
dc.identifier.volume30-
dc.identifier.issue9-
dc.identifier.spage836-
dc.identifier.epage842-
dc.publisher.placeUnited Kingdom-

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