School of Medicine Publications and Presentations
F5_6755A>G, A Nonsynonymous Single-Nucleotide Variation That Substitutes Glycine For Aspartate At Residue 2,194 In The Plasma Blood Clotting Protein Factor V, Is Pleiotropically Associated With Reduced Factor V Coagulant Activity and A Decreased Frailty Index
Document Type
Abstract
Publication Date
2-2023
Abstract
Background: It is well known that coagulation factor V (FV)plays important roles in both hemorrhagic and thromboembolic disorders, and that DNA-sequence variation in the FV gene (F5) maytip the hemostatic balance in either direction. We hypothesized that if such a critical sequence variation exists it would also likely exert a detectable effect on the aging process, where the latter may be quantified using the systemic measure of the physiological decline associated with aging known as the frailty index. OBJECTIVES: We investigated the following three aims: 1) Determine the heritability for the broadly-variable levels of FV coagulant activity (FV:C)observed in human populations, where heritability is a rough measure of the extent of genetic determination of a given trait; 2) Perform anassociation analysis of the set of highly-likely functional variations(HLFVs) to discover genetic determinants influencing FV:C; and 3)Conditional on the results of Aim 2, determine if significant DNA-sequence variations, if any, are also associated with the frailty index.
Methods: Blood samples were obtained by venipuncture after a12–14-hr fast. Plasma was isolated from the 4.5-mLof blood sampled in blue-top vacutainer-tubes containing 0.5 mL of citrate using standard clinical laboratory techniques including double centrifugation at 3,000g for 10 minutes. The Thor Haemostasis Analyzer was used to measure FV:C in quick thawed plasma aliquots using Helena Laboratory’s FV-deficient plasma and PT-based assay.We performed linear mixed model (LMM) analyses to: estimate the heritability; carry out the FV:C association scan; and estimate genetic association with the frailty index. We used the Polyphen program(now available as Polyphen2) to identify the subset of HLFVs—from the overall set of DNA sequence variations genotyped on the Illumina-(human)-exome-24-chip—using the Polyphen score, which ranges from 0 to 1 with 1 being the most deleterious, including the highly-likely deleterious variants that have a Polyphen score >0.9.The frailty index was computed on a set of 31 physiological variables related to health and disease in our study following standard protocol.
Results:We found FV:C has a heritability of 56% (p
Conclusions: From the set of HLFVs genotyped in the present study, we found a ns-SNV that is associated with both reduced FV:Clevels and a decreased frailty index. We suggest that reduced FV:Clevels are associated with a lower risk of thrombosis and concomitant inflammation, which in turn is associated with a decrease in the physiological decline associated with aging as reflected by the inverse association with the frailty index.
Recommended Citation
Nguyen, H., Diego, V., Almeida, M., Jhaveri, S., Peralta, J., Curran, J., Lehman, D., DeFronzo, R., Rajalingam, R., Powell, J., Williams-Blangero, S., Duggirala, R., Blangero, J., & Howard, T. (2023). F5_6755A>G, A Nonsynonymous Single-Nucleotide Variation That Substitutes Glycine For Aspartate At Residue 2,194 In The Plasma Blood Clotting Protein Factor V, Is Pleiotropically Associated With Reduced Factor V Coagulant Activity and A Decreased Frailty Index. American Journal of Hematology, 98(S1), E78–E79. https://doi.org/10.1002/ajh.26841
First Page
E78
Last Page
E79
Publication Title
American Journal of Hematology
DOI
https://doi.org/10.1002/ajh.26841
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
