TY - JOUR
T1 - Classic Thrombophilias and Thrombotic Risk Among Middle-Aged and Older Adults
T2 - A Population-Based Cohort Study
AU - for the Regeneron Genetics Center
AU - Manderstedt, Eric
AU - Lind-Halldén, Christina
AU - Halldén, Christer
AU - Elf, Johan
AU - Svensson, Peter J.
AU - Dahlbäck, Björn
AU - Engström, Gunnar
AU - Melander, Olle
AU - Baras, Aris
AU - Lotta, Luca A.
AU - Zöller, Bengt
N1 - Publisher Copyright:
© 2022 The Authors and Regeneron Genetics Center. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
PY - 2022/2/15
Y1 - 2022/2/15
N2 - BACKGROUND: Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. METHODS AND RESULTS: Factor V Leiden, prothrombin G20210A and protein-coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923–1950, 60% women) who participated in the Malmö Diet and Cancer study (1991–1996). The Human Gene Mutation Database was used to define 68 disease-causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease-causing mutations in the PROC, PROS1, and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3–1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8–1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6–2.0) and HR, 1.6 (95% CI, 1.3–2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6–1.9). HR was 3.9 (95% CI, 3.1–5.0) for carriers of ≥2 thrombophilia variants.CONCLUSIONS: The 5 classic thrombophilias are associated with a dose-graded risk of VTE in middle-aged and older adults. Disease-causing variants in the PROC, PROS1, and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.
AB - BACKGROUND: Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. METHODS AND RESULTS: Factor V Leiden, prothrombin G20210A and protein-coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923–1950, 60% women) who participated in the Malmö Diet and Cancer study (1991–1996). The Human Gene Mutation Database was used to define 68 disease-causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease-causing mutations in the PROC, PROS1, and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3–1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8–1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6–2.0) and HR, 1.6 (95% CI, 1.3–2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6–1.9). HR was 3.9 (95% CI, 3.1–5.0) for carriers of ≥2 thrombophilia variants.CONCLUSIONS: The 5 classic thrombophilias are associated with a dose-graded risk of VTE in middle-aged and older adults. Disease-causing variants in the PROC, PROS1, and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.
KW - epidemiology
KW - genetics
KW - natural anticoagulants
KW - thrombophilia
KW - venous thromboembolism
KW - Anticoagulants
KW - Protein C/genetics
KW - Humans
KW - Middle Aged
KW - Risk Factors
KW - Male
KW - Protein S/genetics
KW - Venous Thromboembolism/diagnosis
KW - Thrombosis/complications
KW - Antithrombins
KW - Prothrombin
KW - Female
KW - Aged
KW - Mutation
KW - Thrombophilia/complications
KW - Factor V/genetics
KW - Cohort Studies
U2 - 10.1161/JAHA.121.023018
DO - 10.1161/JAHA.121.023018
M3 - Article
C2 - 35112923
AN - SCOPUS:85124636679
SN - 2047-9980
VL - 11
SP - 1
EP - 27
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 4
M1 - e023018
ER -
