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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Published in:Human molecular genetics Vol. 30; no. 9; p. 836
Main Authors: Sun, Pengfei, Zhou, Wei, Fu, Yi, Cheung, Chloe Y Y, Dong, Yujun, Yang, Min-Lee, Zhang, He, Jia, Jia, Huo, Yong, Willer, Cristen J, Chen, Y Eugene, Tang, Clara S, Tse, Hung-Fat, Lam, Karen S L, Gao, Wei, Xu, Ming, Yu, Haiyi, Sham, Pak Chung, Zhang, Yan, Ganesh, Santhi K
Format: Journal Article
Language:English
Published: England 28.05.2021
Subjects:
Asians - genetics
Genome-Wide Association Study
Humans
Platelet Count
Polymorphism, Single Nucleotide - genetics
Receptors, Thrombopoietin - genetics
Signal Transduction - genetics
ISSN:1460-2083, 1460-2083
Online Access:Get more information
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Summary: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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ISSN:1460-2083
1460-2083
DOI:10.1093/hmg/ddab062