Construction and validation of a multi-mRNA panel and genetic scores for Krüppel-like factors for acute ischemic stroke

Area of Science:

• Molecular Biology
• Genetics
• Neurology

Background:

• Cellular and animal studies suggest Krüppel-like factors (KLFs) role in acute ischemic stroke (AIS) pathology.
• Epidemiological research on KLFs in AIS etiology and prognosis remains limited.

Purpose of the Study:

• To investigate the contribution of 14 KLFs' leukocyte mRNA expression and 21 genetic tag single nucleotide polymorphisms (tagSNPs) to AIS.
• To evaluate KLFs' role in AIS incidence and patient outcomes.

Main Methods:

• Conducted two case-control studies and three prospective cohort studies involving 360 AIS cases and 363 controls for mRNA analysis.
• Analyzed 21 genetic tagSNPs in 3651 AIS cases and 3900 controls.
• Constructed KLFs mRNA and polygenic risk scores (PRS) to assess discriminative and stratification values.

Main Results:

• A KLFs mRNA score significantly improved AIS discrimination (AUC from 0.724 to 0.871).
• KLFs PRS effectively stratified AIS susceptibility (P_trend < 0.001), with the highest PRS group showing a 42.4% increased AIS risk.
• KLF12 mRNA correlated negatively with modified Rankin Scale (mRS) scores, and KLF12 variants increased AIS-related death risk.

Conclusions:

• KLFs mRNA expression and genetic variants are novel contributors to AIS incidence and prognosis.
• KLFs offer potential as biomarkers for AIS risk stratification and outcome prediction.
• This study provides new insights into the etiological and prognostic roles of KLFs in AIS.