Common coding variant in SERPINA1 increases the risk for large artery stroke.

Area of Science:

• Genetics
• Cardiovascular Disease
• Molecular Biology

Background:

• Large artery atherosclerotic stroke (LAS) heritability is not fully explained by current genetic studies.
• Coding variation represents an underexplored area for LAS genetic risk factors.
• Previous research has not fully elucidated the genetic underpinnings of LAS.

Purpose of the Study:

• To investigate the role of coding variants in Large Artery Atherosclerotic Stroke (LAS) susceptibility.
• To identify novel genetic risk factors for LAS using exome-wide genotyping.
• To functionally characterize identified genetic variants associated with LAS.

Main Methods:

• Exome-wide genotyping using the HumanExome BeadChip array in 3,127 LAS cases and 9,778 controls.
• Statistical association testing to identify risk variants.
• Quantitative microscale thermophoresis and hydrogen/deuterium exchange mass spectrometry to assess protein variant function.

Main Results:

• A novel nonsynonymous variant in SERPINA1 (p.V213A) associated with LAS (P = 5.99E-9, OR = 1.22).
• Histone deacetylase 9 (HDAC9) confirmed as a major LAS risk gene with a 3'-UTR association (rs2023938; P = 7.76E-7, OR = 1.28).
• The SERPINA1 p.V213A variant shows altered binding to neutrophil elastase in lipoprotein-containing plasma and reduced global flexibility.

Conclusions:

• The SERPINA1 p.V213A variant impacts alpha-1 antitrypsin function, potentially influencing LAS risk through interactions with lipoproteins and neutrophil elastase.
• HDAC9 remains a significant genetic contributor to LAS.
• Findings highlight the functional relevance of alpha-1 antitrypsin, lipoproteins, and proteases in atherosclerosis pathogenesis.