Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Identifying genetic susceptibility loci for ischemic stroke is challenging due to the heterogeneity of stroke subtypes.
• This study investigates the association between known genetic variants and neuropathologically defined stroke pathology.

Purpose of the Study:

• To determine if single nucleotide polymorphisms (SNPs) associated with ischemic stroke or its risk factors correlate with neuropathologic findings.
• To examine associations with microscopic infarcts, macroscopic infarcts, and arteriolosclerosis in deceased participants.

Main Methods:

• Neuropathologic examination and genotyping were performed on 755 deceased participants from the Religious Orders Study and Rush Memory and Aging Project.
• 74 candidate SNPs linked to ischemic stroke or risk factors (e.g., diabetes, hypertension, atrial fibrillation) were analyzed.
• Secondary analysis included 93 additional SNPs related to other cardiovascular and cerebrovascular risk factors.

Main Results:

• Diabetes risk variants, including rs7578326 (near IRS1) and rs12779790 (between CAMK1D and CDC123), were strongly associated with both macroscopic and microscopic infarcts.
• The diabetes risk variant rs864745 (JAZF1) was associated with arteriolosclerosis.
• The CDKN2A/B locus (rs2383207) showed association with macroscopic infarct pathology, replicating previous findings.

Conclusions:

• The study implicates several diabetes and other risk variants in stroke-related pathology, highlighting pleiotropic effects.
• Replication of the CDKN2A/B locus association with macroscopic infarcts supports its role in stroke susceptibility.
• Cerebrovascular neuropathologic phenotypes are valuable for genetic dissection of ischemic stroke susceptibility.