Abstract Number: OC 56.5
Meeting: ISTH 2022 Congress
Background: High levels of FVIII and vWF have been showed as independent risk factors for venous thromboembolism. However, little is known about the genetic factors responsible for their increase. In a woman referred to our Thrombosis unit following a venous thrombotic event, very high levels of FVIII and vWF were found at the acute episode and in subsequent measurements. High levels of FVIII and vWF were also detected in other family members, suggesting a possible genetic cause (Figure 1).
Aims: To identify variants/genes associated with high levels of FVIII and vWF.
Methods: Whole-exome sequencing was performed in 12 family members (SureSelect-Agilent). Data were analyzed according to the guidelines of the Broad Institute (https://software.broadinstitute.org/gatk/best-practices/). Variants were annotated (Annovar) and filtered (KGGseq) considering an autosomal dominant inheritance. RNA levels were evaluated in PBMCs by qPCR (Thermo Fisher).
Results: 16 variants were identified in 11 genes, spread over a 8300-Kb region on chromosome 5, including the low frequency rs13158382 located in the promoter of miR-143/145 (Table 1). Since variants in the promoter of miR-143/145 have been reported to affect their expression and reduced levels of miR-145 have been associated with high vWF, the potential correlation between rs13158382 and vWF levels was evaluated. Lower mi-R143/145 levels and higher vWF mRNA levels were measured in 3 family members carrying the rs13158382 variant compared to 3 family members without the variant. Analysis of repository data from the GEUVADIS project confirmed the observed genotype-phenotype correlation. miRVaS tool predicted a structural change of pre-miR-143 with the rs13158382 which might affect Drosha recognition and hence the miRNA processing.
Conclusion(s): In this family-based study, a genetic variant located in the miRNA-143/145 promoter, potentially related to thrombotic event by affecting microRNA expression and levels of vWF and complexed FVIII, was identified. Further investigations are necessary to confirm the mechanisms underlying this genetic predisposition.
To cite this abstract in AMA style:Spena S, Cairo A, Gianniello F, Pappalardo E, Mortarino M, Garagiola I, Martinelli I, Peyvandi F. Insight into genetic predisposition to high plasma levels of Factor VIII (FVIII) and von Willebrand Factor (vWF) in a family with venous thrombosis. [abstract]. https://abstracts.isth.org/abstract/insight-into-genetic-predisposition-to-high-plasma-levels-of-factor-viii-fviii-and-von-willebrand-factor-vwf-in-a-family-with-venous-thrombosis/. Accessed September 29, 2023.
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