Rare variants in MTHFR predispose to occurrence and recurrence of pulmonary embolism
Introduction
As one of the global leading diseases of mortality, pulmonary embolism (PE) causes more than 100,000 deaths annually [1]. The etiology of PE is complicated, stemming from an interplay between genetic and environmental factors. Over the past two decades, risk genetic factors for PE have been thoroughly studied in Western countries and the genetic variants in Factor V Leiden (FVL, rs6025) [2] and prothrombin G20210A (rs1799963) have been identified as major predisposition factors for initiation and development of PE [3]. However, these variants are rare in Asian patients of PE [5], suggesting significant ethnic and genetic differences in PE between Eastern and Western. Furthermore, the mutations in the genes encoding anticoagulants(antithrombin, protein C and protein S) which are the common genetic cause of PE in Asia only accounts for 12.04% of VTE patients [6]. Therefore, the genetic background for PE patients in East Asia remains largely unknown. It is urgently needed to identify other PE susceptibility loci.
Homocysteine (Hcy) is an intermediary amino acid formed by the conversion of methionine to cysteine. Lots of studies has reported that Hyperhomocysteinemia (HHcy) is an important independent procoagulant factor after thrombotic events [[7], [8], [9]] and presents as a risk factor for VTE [[10], [11], [12]]. The 5, 10 methylenetetrahydrofolate reductase (MTHFR) is the key enzyme that catalyzes the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which produces a cosubstrate for the conversion of homocysteine remethylation to methionine [13]. Given the important role of Hcy-MTHFR axis on thrombosis, we hypothesized that the rare variation of MTHFR may be associated with the occurrence and recurrence of PE.
In the current study, we enrolled 254 unprovoked PE patients and analyzed the relationship between rare and pathogenic variants of MTHFR with the level of homocysteine (Hcy) and the recurrence of PE.
Section snippets
Patients
This was a prospective study. We consecutively enrolled unprovoked PE patients(with or without DVT) that occurred without any transient risk factors from January 2013 to December 2018 in FuWai Hospital of Chinese Academy of Medical Sciences, Beijing. PE were diagnosed using computed tomography pulmonary angiography (CTPA) or pulmonary angiogram and deep vein thrombosis was confirmed by lower extremity Doppler ultrasound (DUS) [14]. The exclusion criteria were: PE occurred after prolonged
Participant characteristics
Totally, 764 PE patients were diagnosed in our center and 510 were excluded due to loss to follow-up (n = 4), provoked PE (n = 471) or outpatients (n = 35). A total of 254 PE patients were enrolled in the whole study (Fig. 1), comprised of 129 males and 125 females. The mean age was 57.71 ± 16.51 years. In our study, 10.6% (27/254) of patients had previous PE (Table 1).
Identification of MTHFR as a PE susceptible risk gene
Among the 258 PE patients (including 4 patients who lost to follow-up), we identified 15 cases carrying 8 distinct rare
Discussion
In this study, we genotyped 254 patients with unprovoked PE and identified rare variants of MTHFR as a novel genetic risk factor for PE. The MTHFR rare variants explained up to 5.91% of cases, conferring a 2.92-fold greater odds of the occurrence and 3.82-fold greater odds of recurrence of PE. The circulating Hcy level were increased in PE patients carrying MTHFR rare variants. Allover, these results strongly indicate that rare variants in the MTHFR might contribute to the etiology and
Conclusion
The MTHFR rare variants may increase circulating Hcy levels and predispose to the occurrence and recurrence of PE.
Author statement
1) The scientific guarantor of this publication is Lu Hua and Xiao-Jian Wang.
2) The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.
3) The work was supported by grants from the CAMS Innovation Fund for Medical Sciences(CIFMS)(ID 2017-I2M-3-003), Grant 2018ZX09711001-003-012 from the Drug Innovation Major Project, CAMS Fund for Key Laboratory of Pulmonary Vascular Medicine (2017PT32016).
4) All
Funding
The work was supported by grants from the CAMS Innovation Fund for Medical Sciences (CIFMS) (ID 2017-I2M-3 − 003), Grant 2018ZX09711001-003-012 from the Drug Innovation Major Project, CAMS Fund for Key Laboratory of Pulmonary Vascular Medicine (2017PT32016).
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