Association of MTHFR missense variants with thromboembolic diseases and coagulation factor levels in European populations.

IF 2.6 4区医学 Q2 HEMATOLOGY

Thrombosis Journal Pub Date : 2025-04-08 DOI:10.1186/s12959-025-00711-1

Iyas Daghlas, Mengmeng Wang, Dipender Gill

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引用次数: 0

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.

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欧洲人群中MTHFR错义变异与血栓栓塞性疾病和凝血因子水平的关系

背景：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系的研究受到小样本量的限制。这些变异对凝血因子水平的影响同样不确定。目的：检测MTHFR中C677T和A1298C错义变异与静脉血栓栓塞（VTE）、心脏栓塞性卒中（CES）和循环凝血级联蛋白水平的关系。患者/方法：我们分析了MTHFR错义变异与VTE（81,190例，1419,671例对照）、CES（10,804例，1,234,808例对照）以及来自deCODE （n = 35,559）和UK Biobank （n = 46218）队列的凝血级联蛋白循环水平的遗传关联。这些基因分析的所有参与者都是欧洲血统。我们报告了每个错义变异拷贝的比值比（OR）和贝塔系数。静脉血栓栓塞与因子V Leiden变异的影响进行了比较。结果：A1298C变异可使VTE风险小幅增加（每个等位基因OR: 1.03, 95%可信区间[CI] 1.02-1.04, P = 1.36 × 10- 6）。这种作用比利登因子V对静脉血栓栓塞的作用弱30倍。经多次比较校正后，C677T变异与VTE没有显著相关性（OR 0.99, 95% CI 0.98-1.00, P = 0.04）。经多次比较校正后，两种变异均与CES无关（P≥0.18），也与34种凝血级联蛋白中的任何一种无关。结论：这些数据不支持MTHFR基因检测作为遗传性血栓形成评估的一部分的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Thrombosis Journal Medicine-Hematology

CiteScore

3.80

自引率

3.20%

发文量

审稿时长

16 weeks

期刊介绍： Thrombosis Journal is an open-access journal that publishes original articles on aspects of clinical and basic research, new methodology, case reports and reviews in the areas of thrombosis. Topics of particular interest include the diagnosis of arterial and venous thrombosis, new antithrombotic treatments, new developments in the understanding, diagnosis and treatments of atherosclerotic vessel disease, relations between haemostasis and vascular disease, hypertension, diabetes, immunology and obesity.