Rare Variant Association Analysis Uncovers Involvement of VNN2 in Stroke Outcome

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Stroke outcomes vary significantly due to factors like age, sex, lesion characteristics, and genetics.
• Genome-Wide Association Studies (GWAS) have implicated common variants near genes such as PATJ, PPP1R21, PTCH1, NTN4, and TEK in stroke recovery.
• The specific role of rare genetic variants in stroke recovery remains largely unknown.

Purpose of the Study:

• To identify genetic factors contributing to varying stroke recovery outcomes.
• To investigate the impact of rare genetic variants on post-stroke functional recovery.

Main Methods:

• A pilot study analyzed exomes from 90 patients with extreme recovery outcomes (modified Rankin Scale scores 0-1 vs. 4-5).
• An expanded study sequenced 702 additional samples using targeted next-generation sequencing.
• Retrospective analysis included incidental stroke cases from Spanish hospitals (2000-2018), assessing both continuous and dichotomous modified Rankin Scale scores.

Main Results:

• Rare coding variants in the VNN2 gene were significantly associated with better stroke recovery (P<0.001).
• Six rare VNN2 variants were predicted to impact protein stability.
• One VNN2 variant, located in the active site, may affect protein's electrostatic surface.

Conclusions:

• The VNN2 gene is proposed to influence stroke outcomes by modulating post-stroke inflammation.
• VNN2 variants may affect neutrophil cell adhesion and migration, impacting recovery.
• This research highlights the potential role of rare VNN2 variants in stroke recovery.