The common, VTE-protective, G haplotype of F5 increases factor V-short, TFPI function, and risk of bleeding

The G haplotype is a group of co-inherited single nucleotide variants in the F5 gene that reduce venous thromboembolism (VTE) risk. Even though seven percent of the population is homozygous for the G haplotype (F5-G/G), the underlying mechanism of VTE protection is poorly understood. Using RNA-seq d...

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Published in:	Blood advances
Main Authors:	Sims, Matthew Christopher, Gierula, Magdalena, Stephens, Jonathan C, Tokolyi, Alex, Stefanucci, Luca, Persyn, Elodie, Sun, Luanluan, Collins, Janine H, Davenport, Emma, Di Angelantonio, Emanuele, Downes, Kate, Inouye, Michael, Paul, Dirk S, Thomas, William, Tolios, Alexander, BioResource, Nihr, Ouwehand, Willem H, Gleadall, Nicholas S, Crawley, James T B, Butterworth, Adam S, Frontini, Mattia, Ahnstrom, Josefin
Format:	Journal Article
Language:	English
Published:	United States 04-10-2024
Online Access:	Get full text
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Summary:	The G haplotype is a group of co-inherited single nucleotide variants in the F5 gene that reduce venous thromboembolism (VTE) risk. Even though seven percent of the population is homozygous for the G haplotype (F5-G/G), the underlying mechanism of VTE protection is poorly understood. Using RNA-seq data from 4,651 blood donors in the INTERVAL study we detected a rare excision event at the FV-short splice sites in 5% of F5-G/Gs as compared with 2.16% of homozygotes for the F5 reference sequence (F5-ref) (p=0.003). Highly elevated (~10-fold) FV-short, an FV isoform lacking most of the B-domain, has been linked with increased tissue factor inhibitor alpha (TFPIα) levels in rare hemorrhagic diathesis including East Texas Bleeding Disorder. To ascertain whether the enhanced FV-short splicing seen in F5-G/G INTERVAL participants translated to increased plasma FV-short levels we analyzed plasma samples from 7 F5-G/G and 13 F5-ref individuals in a recall-by-genotype study. A ~2.2-fold higher amount of FV-short was found in a plasma pool from F5-G/G participants as compared with F5-refs (p=0.029), but no difference in total FV levels. Whilst no significant difference in TFPI levels were found, F5-G/Gs showed a ~1.4-fold TFPI-dependent increase in lag time to thrombin generation compared to F5-refs (p=0.0085). Finally, in an analysis of 117,699 UK Biobank participants we discovered that, while being protective against VTE, the G haplotype also confers an increase in bleeding episodes (p=0.011). Our study provides evidence that the effect of the common G haplotype is mediated by the FV-short/TFPI pathway.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2473-9529 2473-9537 2473-9537
DOI:	10.1182/bloodadvances.2024014020