Identification of Regulatory Loci for Megakaryocyte and Hepatocyte Coagulation Factor V Expression in Mice

Abstract

BackgroundFactor V (FV) plays a central role in the coagulation cascade, acting in both a procoagulant and anticoagulant manner. The majority of FV is produced by the liver hepatocytes. In humans, FV is endocytosed by megakaryocytes, whereas in mice, FV is synthesized by megakaryocytes. Little is known about the genomic factors regulating FV transcription in humans and mice. ObjectiveTo investigate genomic regulatory mechanisms for coagulation FV levels in the hepatocytes and megakaryocytes of inbred mice. MethodsPlasma and platelet FV levels were measured via ELISA in 5 mouse strains. A cross between the CAST/EiJ and DBA/2J strains was performed to generate 146 genetically informative F2 mice for analysis of circulating and platelet FV. Plasma and platelet FV levels were measured by ELISA for the F2 mice and whole genome genotyping for each F2 was performed using the TransnetYX MiniMUGA genotyping array. The genotyping and phenotyping data collected from these mice were then analyzed using quantitative trait loci (QTL) analysis. Results and ConclusionsWe identified one significant locus controlling plasma FV levels on Chromosome 1, [~]57.7 million base pairs upstream of the FV structural gene. We also identified a significant QTL for platelets on Chromosome 14 when sex was included as an interactive covariate, with additional suggestive loci present on Chromosomes 15 and 2. Our findings provide foundational information regarding the cell-type and sex-specific control of FV expression, establishing the basis for further investigations aimed at fine-mapping these loci and understanding how FV expression is regulated. EssentialsO_LICoagulation Factor V (FV, gene name F5) is primarily expressed in hepatocytes in humans but in hepatocytes and megakaryocyte/platelets in mice. C_LIO_LIPlasma and megakaryocyte/platelet F5 expression varies significantly between inbred mouse strains. C_LIO_LIWe identified significant loci controlling plasma and platelet F5 expression in mice. Platelet F5 expression is influenced by biological sex. C_LI