Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations
Abstract Background Investigations of the association between missense variants in the methylenetetrahydrofolate reductase (MTHFR) gene and thromboembolic diseases have been limited by small sample sizes. The effect of these variants on coagulation factor levels remains similarly uncertain. Objectiv...
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BMC
2025-04-01
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| Series: | Thrombosis Journal |
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| Online Access: | https://doi.org/10.1186/s12959-025-00711-1 |
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| author | Iyas Daghlas Mengmeng Wang Dipender Gill |
| author_facet | Iyas Daghlas Mengmeng Wang Dipender Gill |
| author_sort | Iyas Daghlas |
| collection | DOAJ |
| description | Abstract Background Investigations of the association between missense variants in the methylenetetrahydrofolate reductase (MTHFR) gene and thromboembolic diseases have been limited by small sample sizes. The effect of these variants on coagulation factor levels remains similarly uncertain. Objectives To test the association of the C677T and A1298C missense variants in MTHFR with risk of venous thromboembolism (VTE), cardioembolic stroke (CES), and circulating coagulation cascade protein levels. Patients/Methods We analyzed genetic associations of MTHFR missense variants with VTE (81,190 cases and 1,419,671 controls), CES (10,804 cases and 1,234,808 controls), and circulating levels of coagulation cascade proteins from the deCODE (n = 35,559) and UK Biobank (n = 46,218) cohorts. All participants in these genetic analyses were of European ancestry. We report odds ratios (OR) and beta coefficients per copy of the missense variant. VTE associations were compared to the effect of the Factor V Leiden variant. Results The A1298C variant conferred a small increased risk of VTE (OR per allele: 1.03, 95% confidence interval [CI] 1.02–1.04, P = 1.36 × 10− 6). This effect was 30-fold weaker than the effect of Factor V Leiden on VTE. After correction for multiple comparisons, the C677T variant did not demonstrate a significant association with VTE (OR 0.99, 95% CI 0.98-1.00, P = 0.04). Neither variant was associated with CES (P ≥ 0.18), nor with any of the 34 coagulation cascade proteins after correction for multiple comparisons. Conclusions These data do not support a role for MTHFR genetic testing as part of an inherited thrombophilia evaluation. |
| format | Article |
| id | doaj-art-5d05c2597ff54688839cc52085ad84fa |
| institution | DOAJ |
| issn | 1477-9560 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Thrombosis Journal |
| spelling | doaj-art-5d05c2597ff54688839cc52085ad84fa2025-08-20T03:06:57ZengBMCThrombosis Journal1477-95602025-04-012311510.1186/s12959-025-00711-1Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populationsIyas Daghlas0Mengmeng Wang1Dipender Gill2Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San FranciscoDepartment of Neurology, The Third Affiliated Hospital of Soochow UniversityDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonAbstract Background Investigations of the association between missense variants in the methylenetetrahydrofolate reductase (MTHFR) gene and thromboembolic diseases have been limited by small sample sizes. The effect of these variants on coagulation factor levels remains similarly uncertain. Objectives To test the association of the C677T and A1298C missense variants in MTHFR with risk of venous thromboembolism (VTE), cardioembolic stroke (CES), and circulating coagulation cascade protein levels. Patients/Methods We analyzed genetic associations of MTHFR missense variants with VTE (81,190 cases and 1,419,671 controls), CES (10,804 cases and 1,234,808 controls), and circulating levels of coagulation cascade proteins from the deCODE (n = 35,559) and UK Biobank (n = 46,218) cohorts. All participants in these genetic analyses were of European ancestry. We report odds ratios (OR) and beta coefficients per copy of the missense variant. VTE associations were compared to the effect of the Factor V Leiden variant. Results The A1298C variant conferred a small increased risk of VTE (OR per allele: 1.03, 95% confidence interval [CI] 1.02–1.04, P = 1.36 × 10− 6). This effect was 30-fold weaker than the effect of Factor V Leiden on VTE. After correction for multiple comparisons, the C677T variant did not demonstrate a significant association with VTE (OR 0.99, 95% CI 0.98-1.00, P = 0.04). Neither variant was associated with CES (P ≥ 0.18), nor with any of the 34 coagulation cascade proteins after correction for multiple comparisons. Conclusions These data do not support a role for MTHFR genetic testing as part of an inherited thrombophilia evaluation.https://doi.org/10.1186/s12959-025-00711-1Cardioembolic strokeMTHFRProteomicsUK biobankVenous thromboembolism |
| spellingShingle | Iyas Daghlas Mengmeng Wang Dipender Gill Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations Thrombosis Journal Cardioembolic stroke MTHFR Proteomics UK biobank Venous thromboembolism |
| title | Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations |
| title_full | Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations |
| title_fullStr | Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations |
| title_full_unstemmed | Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations |
| title_short | Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations |
| title_sort | association of mthfr missense variants with thromboembolic diseases and coagulation factor levels in european populations |
| topic | Cardioembolic stroke MTHFR Proteomics UK biobank Venous thromboembolism |
| url | https://doi.org/10.1186/s12959-025-00711-1 |
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