Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle‐aged and older adults: A population‐based cohort study

• Published in: Research and practice in thrombosis and haemostasis Vol. 6; no. 7; pp. e12842 - n/a
• Main Authors: Manderstedt, Eric, Lind‐Halldén, Christina, Halldén, Christer, Elf, Johan, Svensson, Peter J., Engström, Gunnar, Melander, Olle, Baras, Aris, Lotta, Luca A., Zöller, Bengt, Abecasis, Goncalo, Cantor, Michael, Coppola, Giovanni, Economides, Aris, Overton, John D., Reid, Jeffrey G., Shuldiner, Alan, Beechert, Christina, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Lattari, Michael, Lopez, Alexander, Schleicher, Thomas D., Padilla, Maria Sotiropoulos, Widom, Louis, Wolf, Sarah E., Pradhan, Manasi, Manoochehri, Kia, Ulloa, Ricardo H., Bai, Xiaodong, Balasubramanian, Suganthi, Blumenfeld, Andrew, Boutkov, Boris, Eom, Gisu, Habegger, Lukas, Hawes, Alicia, Khalid, Shareef, Krasheninina, Olga, Lanche, Rouel, Mansfield, Adam J., Maxwell, Evan K., Nafde, Mrunali, O’Keeffe, Sean, Orelus, Max, Panea, Razvan, Polanco, Tommy, Rasool, Ayesha, Salerno, William, Staples, Jeffrey C., Jones, Marcus B., Mighty, Jason, Mitnaul, Lyndon J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2022; Elsevier Limited; John Wiley and Sons Inc; Elsevier
• Subjects: adult; Anticoagulants; Basic Medicine; blood clotting; blood coagulation; Brief Report; Brief Reports; Cardiac and Cardiovascular Systems; Cardiology and Cardiovascular Disease; Clinical Medicine; Cohort analysis; deep vein thrombosis; exosome; female; Gene expression; gene frequency; gene mutation; genetic analysis; genetic screening; genetic variation; Genomes; haplotype; Hematologi; Hematology; human; ICD-10; ICD-9; Kardiologi; Kardiologi och kardiovaskulära sjukdomar; Klinisk medicin; loss of function mutation; major clinical study; male; Medical and Health Sciences; Medical Genetics; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; missense mutation; molecular epidemiology; Older people; Population; Population-based studies; principal component analysis; single nucleotide polymorphism; Thromboembolism; thrombophilia; thrombophlebitis; Thrombosis; tissue factor pathway inhibitor; vein thrombosis; Veins & arteries; venous thromboembolism; whole exome sequencing; Sweden; molecular epidemiology; thrombophilia; genetic variation; blood coagulation; venous thromboembolism
• ISSN: 2475-0379; 2475-0379
• DOI: 10.1002/rth2.12842

Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population‐based cohort of middle‐aged and older adults. The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss‐of‐function or nonbenign (PolyPhen‐2) missense variants with minor allele frequency less than 0.1%. No common variant was associated with VTE. Nine rare variants (two loss‐of‐function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and ancestry showed a hazard ratio of 2.9 (95% CI, 1.2–7.1) for rare qualifying variants. Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene. [Display omitted]