Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study
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 olde...
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| Format: | Article |
| Language: | English |
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Wiley
2022-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.121.023018 |
| _version_ | 1827978588165505024 |
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| author | Eric Manderstedt Christina Lind‐Halldén Christer Halldén Johan Elf Peter J. Svensson Björn Dahlbäck Gunnar Engström Olle Melander Aris Baras Luca A. Lotta Bengt Zöller |
| author_facet | Eric Manderstedt Christina Lind‐Halldén Christer Halldén Johan Elf Peter J. Svensson Björn Dahlbäck Gunnar Engström Olle Melander Aris Baras Luca A. Lotta Bengt Zöller |
| author_sort | Eric Manderstedt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T21:23:13Z |
| format | Article |
| id | doaj.art-ea61244395784f04806e757e89ec07b6 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-09T21:23:13Z |
| publishDate | 2022-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-ea61244395784f04806e757e89ec07b62023-03-28T04:20:06ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802022-02-0111410.1161/JAHA.121.023018Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort StudyEric Manderstedt0Christina Lind‐Halldén1Christer Halldén2Johan Elf3Peter J. Svensson4Björn Dahlbäck5Gunnar Engström6Olle Melander7Aris Baras8Luca A. Lotta9Bengt Zöller10Department of Environmental Science and Bioscience Kristianstad University Kristianstad SwedenDepartment of Environmental Science and Bioscience Kristianstad University Kristianstad SwedenDepartment of Environmental Science and Bioscience Kristianstad University Kristianstad SwedenDepartment of Clinical Sciences Lund UniversitySkåne University Hospital Malmö SwedenDepartment of Clinical Sciences Lund UniversitySkåne University Hospital Malmö SwedenDepartment of Translational Medicine Lund UniversitySkåne University Hospital Malmö SwedenDepartment of Clinical Sciences Lund UniversitySkåne University Hospital Malmö SwedenDepartment of Clinical Sciences Lund UniversitySkåne University Hospital Malmö SwedenRegeneron Genetics Center Tarrytown NYRegeneron Genetics Center Tarrytown NYCenter for Primary Health Care Research Lund University and Region Skåne Malmö SwedenBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.121.023018epidemiologygeneticsnatural anticoagulantsthrombophiliavenous thromboembolism |
| spellingShingle | Eric Manderstedt Christina Lind‐Halldén Christer Halldén Johan Elf Peter J. Svensson Björn Dahlbäck Gunnar Engström Olle Melander Aris Baras Luca A. Lotta Bengt Zöller Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease epidemiology genetics natural anticoagulants thrombophilia venous thromboembolism |
| title | Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study |
| title_full | Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study |
| title_fullStr | Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study |
| title_full_unstemmed | Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study |
| title_short | Classic Thrombophilias and Thrombotic Risk Among Middle‐Aged and Older Adults: A Population‐Based Cohort Study |
| title_sort | classic thrombophilias and thrombotic risk among middle aged and older adults a population based cohort study |
| topic | epidemiology genetics natural anticoagulants thrombophilia venous thromboembolism |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.121.023018 |
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