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. 2020 Jul;105(7):e365-e369.
doi: 10.3324/haematol.2019.237750. Epub 2019 Nov 7.

Rare variants lowering the levels of coagulation factor X are protective against ischemic heart disease

Elvezia Maria Paraboschi  1   2 , Amit Vikram Khera  3   4   5 , Piera Angelica Merlini  6 , Laura Gigante  7 , Flora Peyvandi  8   9 , Mark Chaffin  3   4   5 , Marzia Menegatti  8 , Fabiana Busti  10 , Domenico Girelli  10 , Nicola Martinelli  10 , Oliviero Olivieri  10 , Sekar Kathiresan  3   4   5 , Diego Ardissino  7 , Rosanna Asselta  1   2 , Stefano Duga  1   2
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Free PMC article

Rare variants lowering the levels of coagulation factor X are protective against ischemic heart disease

Elvezia Maria Paraboschi et al. Haematologica. 2020 Jul.
Free PMC article
No abstract available

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Figures

Figure 1
Figure 1
Role of coagulation factor X/activated factor x in blood coagulation and atherothrombosis. (A) The panels show a simplified overview of blood coagulation, which has been sub-divided in initiation, propagation, amplification, and clot formation phases. Clotting factors are indicated using Roman numbers, with the corresponding active form specified by “a”. Pharmacological inhibitors specifically targeting FXa are also listed. FX: factor X; FXa: activated factor X; vWF: von Willebrand factor; TF: tissue factor. (B) The figure shows a schematic representation of an artery, highlighting the different stages of the atherothrombotic process (from left to right). (C) The scheme shows in more details the processes characterizing endothelial cell activation up to plaque rupture in atherothrombosis. Thrombin (IIa) and FXa play a fundamental role through the interactions with PAR (protease-activated receptors). The figure was created using BioRender (https://biorender.com/).
Figure 2
Figure 2
Rare variants lowering the levels of coagulation factor X are protective against early-onset myocardial infarction. This study was approved by the Institutional Ethical Committees of the participating hospitals. All study participants signed an informed consent and gave information about their clinical history, and cardiovascular risk factors. (A) Association of the burden of rare mutations in the F10 gene with the risk for early-onset myocardial infarction (MI). Summary allele counts and carrier frequencies are shown (calculation performed on 1,791 cases and 1,750 controls); only variants with minor allele frequency less than 1% were considered in the burden analysis. The “deleterious” set is defined by missense variations predicted to be possibly damaging by all five algorithms used (LRT score, MutationTaster, PolyPhen-2 HumDiv, PolyPhen-2 HumVar, and SIFT) and those annotated as responsible for factor X (FX) deficiency in publicly available databases. The “non-synonymous” set comprises all the missense variants; the “synonymous” set comprises the synonymous variants. All the tests were run using EPACTS. T1: alleles carrying variants with minor allele frequency less than 1%; Freq (%): percentage of cases or controls carrying a T1 allele; OR: odds ratio; CI: confidence interval. (B) FX coagulant activity (FX:C; light grey bars) and antigen levels (FX:Ag; dark grey bars) were measured in the plasma of subjects carrying the newly identified missense variants (predicted to be damaging by all prediction programs). All analyzed subjects were not taking any anticoagulant drugs at time of the blood drawn. The normal range for FX:C is between 66% and 126%, and is represented by a light grey box delimited by dashed lines in the graph. The normal range for FX:Ag is between 70% and 150% (represented by solid lines). The protein variations are referred to the transcript NM_000504.3. Details on FX:C and FX:Ag measurements are specified in the Online Supplementary Materials and Methods. (C) Ribbon diagrams of secondary/tertiary structures of the human FXa are shown. The positions of 3 of 4 newly identified missense mutations are reported (the region harboring the p.E54G variant is not included in the FXa structure). The position of the “frequent” p.E142K variant is also shown. The color code indicates the different FXa chains (shades of blue and green point to the light and heavy chains, respectively). The protein surface is represented to show that 3 of 4 mutated residues are exposed to the solvent. Diagrams were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics (http://www.rbvi.ucsf.edu/) software and the Protein Data Bank 1ezq entry. Image credits: Dr. Sonia Caccia (University of Milan; sonia.caccia@unimi.it).
Figure 3
Figure 3
The F10 p.E142K (rs61753266) variant is protective against myocardial infarction/coronary artery disease. (A) Association analysis. The association between the presence of the p.E142K variant and the myocardial infarction/coronary artery disease (MI/CAD) status (Fisher’s exact test) was tested in two Italian cohorts (ATVB and VHS). Summary allele counts and carrier frequencies are shown. T1: alleles carrying the p.E142K variant; Freq (%): percentage of cases or controls carrying a T1 allele; OR: odds ratio; CI: confidence interval; ATVB: The Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group; VHS: Verona Heart Study. (B) Meta-analysis. The meta-analysis was performed using the Mantel-Haenszel fixed-effects model, as already described for rare variants (see the Online Supplementary Materials and Methods). The squares indicate the estimated OR for carriers, compared with non-carriers, in each group. The diamond indicates the combined results.
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