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

Area of Science:

• Genetics
• Cardiovascular Medicine
• Thrombosis

Background:

• Rare genetic variants contribute to unprovoked pulmonary embolism (PE), but known risk genes explain only a small fraction of cases.
• The methylenetetrahydrofolate reductase (MTHFR) gene is a potential candidate for investigation in PE etiology.
• Understanding genetic predispositions is crucial for improving PE risk assessment and management.

Purpose of the Study:

• To investigate the association between rare variants in the methylenetetrahydrofolate reductase (MTHFR) gene and the occurrence of unprovoked pulmonary embolism (PE).
• To evaluate the impact of MTHFR rare variants on the long-term clinical outcomes and recurrence rates of PE.

Main Methods:

• Whole exome sequencing was employed to identify rare MTHFR variants in 258 unprovoked PE cases and 11,451 controls.
• Genotype-phenotype correlations were assessed, including plasma homocysteine levels.
• Clinical outcomes, particularly recurrent PE events, were monitored during a 3.0-year follow-up period.

Main Results:

• MTHFR rare variants were significantly more prevalent in PE cases (5.81%) than in controls (2.10%), indicating a 2.87-fold increased odds of PE.
• Patients with MTHFR rare variants exhibited higher plasma homocysteine levels.
• Recurrent PE occurred more frequently in patients with MTHFR rare variants (53.3%) compared to those without (23.0%).

Conclusions:

• Rare variants in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with an increased risk of pulmonary embolism (PE) occurrence.
• MTHFR rare variants may also contribute to a higher incidence of recurrent PE events.
• These findings suggest a potential role for MTHFR genetic testing in evaluating PE risk and prognosis.