Abstract
Inflammation has been associated with atherothrombotic stroke and recently with cardioembolic stroke. Different genetic risk factors have been specifically associated with the subtypes of ischemic stroke (cardioembolic, atherothrombotic, and lacunar). However, there are no studies that have generated genetic risk scores for the different subtypes of ischemic stroke using polymorphisms associated with inflammation. Methods. We have analyzed 68 polymorphisms of 30 inflammatory mediator genes in 2,685 subjects: 1,987 stroke cases and 698 controls. We generated a genetic scoring system with the most significant polymorphisms weighted by the odds ratio of every polymorphism and taken into consideration the stroke subtype. Results. Three polymorphisms, rs1205 (CRP gene), rs1800779, and rs2257073 (NOS3 gene), were associated with cardioembolic stroke (p value <0.05). The score generated was only associated with the cardioembolic stroke subtype (p value: 0.001) and was replicated in an independent cohort (p value: 0.017). The subjects with the highest score presented a cardioembolic stroke in 92.2% of the cases (p value: 0.002). Conclusion. The genetics of inflammatory markers is more closely associated with cardioembolic strokes than with atherothrombotic or lacunar strokes. The genetic risk scoring system could be useful in the prediction and differentiation of ischemic stroke; however, it might be specific to particular ischemic stroke subtypes.
Highlights
Ischemic stroke is a leading cause of death and disability worldwide [1]
These studies have proven difficult to replicate for a number of reasons: it is because they may be false positive associations; it is because of the fact that each gene may only contribute partially to overall heritability; or it is because the studies did not study the ischemic stroke subtypes separately [4, 5]
We hypothesize that the trend of association between the score and undetermined stroke is due to a high percentage of undetermined strokes that are cardioembolic strokes that have not been correctly diagnosed
Summary
Ischemic stroke is a leading cause of death and disability worldwide [1]. twin and familial aggregation studies have revealed a significant genetic component involved in the etiology of stroke, not all of the genetic risk factors responsible for this heritability have been determined [2]. Candidate gene association studies have permitted the identification of several other candidate genes that may be associated with ischemic stroke, such as APOE, IL6, MTHFR, and TNFα [2]. A meta-analysis of GWAS on ischemic stroke identified the ZFHX3 gene on Mediators of Inflammation chromosome 16q22 as a locus associated with atrial fibrillation and cardioembolic stroke [6, 7]. Another ischemic stroke-related GWAS showed intriguing results, including the identification of risk variants for atrial fibrillation and cardioembolic stroke on chromosome 4q25 near the PITX2 gene [8] and for atherothrombotic stroke in the 9p21 locus [9]. The association of ischemic stroke with ZFHX3, PITX2, the 9p21 locus, and HDAC9 was verified in the collaborative METASTROKE study in which these loci were found to be specific to particular stroke subtypes [11]
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