Rare variants in MTHFR predispose to occurrence and recurrence of pulmonary embolism

Rare genetic variants play a critical role in unprovoked pulmonary embolism (PE). However, the known risk genes only account a small proportion of patients with PE. The objective of this study was to investigate the relationship between the rare variants of gene encoding methylenetetrahydrofolate reductase (MTHFR) and the initiation and long-term clinical outcomes of PE. The rare variants of MTHFR were detected by whole exome sequencing of DNA from 258 unprovoked PE cases and 11,451 controls. Correlation of genotype and clinical phenotype and outcome were evaluated at baseline and after follow-up. MTHFR rare variants were found in 15 of 258 cases (5.81%) and 241 of 11,451 controls (2.10%), conferring 2.87-fold greater odds of the PE occurrence (OR = 2.87, 95% CI = 1.68–4.91, P = 5.6 × 10−5, chi-square test). The patients with MTHFR rare variants had higher plasma level of homocysteine than those without. During a follow-up of 3.0 years, a total of 84 events were identified. The recurrent PE (two or more events of PE) were significantly higher in patients carrying MTHFR rare variants (8/15, 53.3%) compared with those without (55/239, 23.0%) (P = 0.023). We speculate that MTHFR rare variants may increase the occurrence and recurrence of PE. •Patients carrying MTHFR rare variants had higher plasma Hcy level than those without rare variants.•Rare variants of MTHFR were not only associated with the occurrence, but also closely associated with recurrence of PE.