CD40-1C>T Polymorphism (rs1883832) is Associated with Brain Vessel Reocclusion after Fibrinolysis in Ischemic Stroke

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 β-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.

KEYWORDS::

• CD40
• matrix γ-carboxyglutamic acid protein
• pharmacogenetics
• reocclusion
• stroke
• tissue plasminogen activator

Acknowledgements

The authors are deeply grateful to all study participants, neurologists and nurses of the Stroke Unit from Vall d‘Hebron Hospital (Barcelone, Spain) for their contributions. We are also grateful for excellent technical support from A Penalba, L Ortega, C Boada, JL Peiro and S García-Menéndez. We would also like to thank the National Center for Genotyping (CeGen, Barcelona, Spain) for their excellent technical assistance. This study is part of the project Geno-tPA. The Neurovascular Research Laboratory takes part in the International Stroke Genetics Consortium ISGC and the Spanish stroke research network RENEVAS (RD06/0026/0010).

Financial & competing interests disclosure

This study was funded by grants from the Spanish government (Geno-tPA project-FIS PJ060586), Mutua Madrileña (2006) and Ramón Areces (2006) Foundations. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was funded by grants from the Spanish government (Geno-tPA project-FIS PJ060586), Mutua Madrileña (2006) and Ramón Areces (2006) Foundations. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.