Document Detail

Genetic susceptibility for ischemic infarction and arteriolosclerosis based on neuropathologic evaluations.
MedLine Citation:
PMID:  24135527     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Recent genetic studies of stroke and related risk factors have identified a growing number of susceptibility loci; however, the relationship of these alleles to ischemic stroke is unknown. The challenge in finding reproducible loci of ischemic stroke susceptibility may be in part related to the etiologic heterogeneity in clinically defined stroke subtypes. In this study, we tested whether known single nucleotide polymorphisms (SNPs) associated with stroke or putative stroke risk factors are associated with neuropathologically defined micro- or macroscopic infarcts and with arteriolosclerosis.
METHODS: Measures of neuropathology and genotyping were available from 755 deceased participants from the Religious Orders Study and the Rush Memory and Aging Project. All donated brains were examined by a board-certified neuropathologist using standardized protocol for the presence of microscopic infarct, macroscopic infarct and arteriolosclerosis (lipohyalinosis). In primary analysis, 74 candidate SNPs previously associated (p < 5 × 10(-8)) with ischemic stroke or known risk factors, including atrial fibrillation (AF), hypertension, diabetes, low-density lipoprotein (LDL) level and carotid artery stenosis, were evaluated for association with neuropathologic endpoints. We performed a secondary exploratory analysis to include 93 additional SNPs associated with putative ischemic stroke risk factors including SNPs associated with high-density lipoprotein (HDL), triglyceride serum levels, myocardial infarction (MI), coronary artery disease and cerebral white matter disease. Regression models relating SNPs to cerebrovascular neuropathology were adjusted for age at death, gender and cohort membership.
RESULTS: The strongest associations seen for both macroscopic and microscopic infarcts were risk variants associated with diabetes. The diabetes risk variant rs7578326 located near the IRS1 locus was associated with both macroscopic (OR = 0.73, p = 0.011) and microscopic (OR = 0.71, p = 0.009) infarct pathology. Another diabetes susceptibility locus (rs12779790) located between the calcium/calmodulin-dependent protein kinase ID (CAMK1D) and cell division cycle 123 homolog (CDC123) genes is also associated with both macroscopic (OR = 1.40, p = 0.0292) and microscopic infarcts (OR = 1.43, p = 0.0285). The diabetes risk variant rs864745 within JAZF1 was associated with arteriolosclerosis (OR = 0.80, p = 0.014). We observed suggestive associations with the diabetes risk variant rs7961581 (p = 0.038; between TSPAN8 and LGR5) and rs5215 (p = 0.043; KCNJ11), the LDL risk variant rs11206510 (p = 0.045; PCSK9), as well as the AF risk locus ZFHX3. The CDKN2A/B locus (rs2383207, 9p21), identified initially as a susceptibility allele for MI and recently implicated in large vessel stroke, was associated with macroscopic infarct pathology in our autopsy cohort (OR = 1.26, p = 0.031).
CONCLUSION: Our results suggest replication of the candidate CDKN2A/B stroke susceptibility locus with directly measured macroscopic stroke neuropathology, and further implicate several diabetes and other risk variants with secondary, pleiotropic associations to stroke-related pathology in our autopsy cohort. When coupled with larger sample sizes, cerebrovascular neuropathologic phenotypes will likely be powerful tools for the genetic dissection of susceptibility for ischemic stroke.
S H-Y Chou; J M Shulman; B T Keenan; E A Secor; A S Buchman; J Schneider; D A Bennett; P L De Jager
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-10-12
Journal Detail:
Title:  Cerebrovascular diseases (Basel, Switzerland)     Volume:  36     ISSN:  1421-9786     ISO Abbreviation:  Cerebrovasc. Dis.     Publication Date:  2013  
Date Detail:
Created Date:  2013-10-18     Completed Date:  2014-06-18     Revised Date:  2014-10-16    
Medline Journal Info:
Nlm Unique ID:  9100851     Medline TA:  Cerebrovasc Dis     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  181-8     Citation Subset:  IM    
Copyright Information:
© 2013 S. Karger AG, Basel.
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MeSH Terms
Aged, 80 and over
Arteriolosclerosis / genetics*
Genetic Predisposition to Disease*
Genetic Variation / genetics
Genome-Wide Association Study / methods
Infarction / genetics*
Middle Aged
Polymorphism, Single Nucleotide / genetics*
Risk Factors
Stroke / genetics
Grant Support
K01 AG024079/AG/NIA NIH HHS; K01 AG024079/AG/NIA NIH HHS; K08 AG034290/AG/NIA NIH HHS; K08AG034290/AG/NIA NIH HHS; K23 NS073806/NS/NINDS NIH HHS; K23NS073806/NS/NINDS NIH HHS; P30 AG010161/AG/NIA NIH HHS; P30 AG019610/AG/NIA NIH HHS; P30 AG10161/AG/NIA NIH HHS; P30 AG19610/AG/NIA NIH HHS; P50 AG016574/AG/NIA NIH HHS; P50 AG16574/AG/NIA NIH HHS; P50 AG23173/AG/NIA NIH HHS; R01 AG011101/AG/NIA NIH HHS; R01 AG015819/AG/NIA NIH HHS; R01 AG017917/AG/NIA NIH HHS; R01 AG023173/AG/NIA NIH HHS; R01 AG023193/AG/NIA NIH HHS; R01 AG030146/AG/NIA NIH HHS; R01 AG11101/AG/NIA NIH HHS; R01 AG15819/AG/NIA NIH HHS; R01 AG17917/AG/NIA NIH HHS; R01 NS059873/NS/NINDS NIH HHS; R01 NS059873/NS/NINDS NIH HHS; R01AG023193/AG/NIA NIH HHS; R01AG30146/AG/NIA NIH HHS; U01 AG016976/AG/NIA NIH HHS; U01 AG016976/AG/NIA NIH HHS; U24 NS051872/NS/NINDS NIH HHS; U24NS051872/NS/NINDS NIH HHS
Comment In:
Cerebrovasc Dis. 2013;36(3):189   [PMID:  24135528 ]

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