Daghlas Iyas, Wang Mengmeng, Gill Dipender
Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
Department of Neurology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
Thromb J. 2025 Apr 8;23(1):29. doi: 10.1186/s12959-025-00711-1.
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.
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.
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). 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.
These data do not support a role for MTHFR genetic testing as part of an inherited thrombophilia evaluation.
亚甲基四氢叶酸还原酶（MTHFR）基因错义变异与血栓栓塞性疾病之间关联的研究因样本量小而受到限制。这些变异对凝血因子水平的影响同样仍不确定。
检测MTHFR基因中C677T和A1298C错义变异与静脉血栓栓塞症（VTE）、心源性栓塞性卒中（CES）风险以及循环凝血级联蛋白水平之间的关联。
患者/方法：我们分析了MTHFR错义变异与VTE（81190例病例和1419671例对照）、CES（10804例病例和1234808例对照）以及来自deCODE队列（n = 35559）和英国生物银行队列（n = 46218）的循环凝血级联蛋白水平之间的遗传关联。这些遗传分析中的所有参与者均为欧洲血统。我们报告每个错义变异拷贝的比值比（OR）和β系数。将VTE关联与因子V莱顿变异的影响进行比较。
A1298C变异使VTE风险略有增加（每个等位基因的OR：1.03，95%置信区间[CI] 1.02 - 1.04，P = 1.36×10）。这种效应比因子V莱顿对VTE的效应弱30倍。在进行多重比较校正后，C677T变异与VTE未显示出显著关联（OR 0.99，95% CI 0.98 - 1.00，P = 0.04）。两种变异均与CES无关（P≥0.18），在进行多重比较校正后，也与34种凝血级联蛋白中的任何一种均无关。
这些数据不支持将MTHFR基因检测作为遗传性易栓症评估的一部分。
