CD40-1C>T polymorphism (rs1883832) is associated with brain vessel reocclusion after fibrinolysis in ischemic stroke

Pharmacogenomics. 2010 Jun;11(6):763-72. doi: 10.2217/pgs.10.44.

Abstract

Aims: To find genetic predictors of reocclusion after successful fibrinolytic therapy during the acute phase of ischemic stroke.

Patients & methods: This was a case-case prospective study analyzing 236 polymorphisms in a cohort of 222 patients treated with tissue plasminogen activator, from which 16 patients suffered a reocclusion event (7.2%). A predictive scale was generated using independent polymorphisms with a dominant/recessive model and tandem occlusion, weighted by their beta-coefficients in logistic regression.

Results: Using a dominant/recessive model, the rs1800801 SNP from the MGP gene (odds ratio [OR]: 15.25; 95% CI: 2.23-104.46; adjusted p = 0.006) and the rs1883832 SNP from CD40 gene (OR: 0.077; 95% CI: 0.009-0.66; adjusted p = 0.019) were independently associated with reocclusion after logistic regression adjustment by clinical predictors. In an additive model, only the rs1883832 SNP (OR: 4.43; 95% CI: 1.62-12.15; adjusted p = 0.004) was related to reocclusion occurrence. The predictive model that was generated stratified the reocclusion risk from less than 1% to more than 70%. Reocclusions were associated with neurological worsening at 24 h (patients with reocclusion: 26.7%, versus patients without reocclusion: 4.9%; p = 0.002), as it was seen for MGP -7A>G (AA: 17.2% vs AG+GG: 4.5%; p = 0.027), but not for CD40 1C>T (CC: 4.5% vs CT+TT: 7.7%; p = 0.565). There was an association between CD40 -1C>T genotype and CD40 transcriptional activity in peripheral blood mononuclear cells (median expression values TT: 65.75%, CT: 70.80%, CC: 96.00%; p = 0.023). However, CD40 soluble fraction was not a useful biomarker of reocclusion status.

Conclusion: An association was found between MGP -7A>G and CD40 -1C>T polymorphisms, and reocclusion risk. The predictive scale that was generated permits the stratification of patients by their reocclusion risk with higher accuracy than clinical parameters alone.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Biomarkers / blood
  • Brain / blood supply
  • Brain / drug effects
  • Brain / metabolism
  • Brain Ischemia / complications
  • Brain Ischemia / diagnostic imaging
  • Brain Ischemia / epidemiology
  • Brain Ischemia / genetics*
  • Calcium-Binding Proteins / genetics
  • Carotid Arteries / diagnostic imaging
  • Extracellular Matrix Proteins / genetics
  • Female
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / therapeutic use*
  • Humans
  • Logistic Models
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Prospective Studies
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk
  • Stroke / diagnostic imaging
  • Stroke / drug therapy
  • Stroke / epidemiology
  • Stroke / etiology
  • Stroke / genetics*
  • TNF Receptor-Associated Factor 3 / blood
  • TNF Receptor-Associated Factor 3 / genetics*
  • Tissue Plasminogen Activator / administration & dosage
  • Tissue Plasminogen Activator / therapeutic use*
  • Treatment Outcome
  • Ultrasonography, Doppler

Substances

  • Biomarkers
  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • Fibrinolytic Agents
  • TNF Receptor-Associated Factor 3
  • TRAF3 protein, human
  • matrix Gla protein
  • Tissue Plasminogen Activator