Abstract
Background and PurposeCoagulation factor XI (FXI) has an important role in the propagation and stabilization of a thrombus upon vessel injury. High FXI levels have been implicated in thrombotic diseases including ischemic stroke. The aim of our study was to investigate whether FXI gene (F11) variants are associated with ischemic stroke.MethodsThe discovery sample, the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), included 844 patients with ischemic stroke and 668 controls, all aged 18-70 years. Replication was performed in the Lund Stroke Register (LSR) and Malmö Diet and Cancer study (MDC), together including 1213 patients and 788 controls up to 70 years of age, and in total 3145 patients and 1793 controls (18-102 years). Seven F11 single-nucleotide polymorphisms (SNPs) were selected using a tagging approach.ResultsThe SNPs rs3733403, rs925451, and rs1593 showed independent associations with overall ischemic stroke in SAHLSIS, ORs of 0.74 (95% CI 0.59-0.94), 1.24 (95% CI 1.06-1.46), and 0.70 (95% CI 0.55-0.90), respectively. The association for rs925451 was replicated in the LSR and MDC sample in a pre-specified analysis of subjects aged 70 years or younger, OR of 1.16 (95% CI 1.00-1.34), whereas no SNP was replicated when all ages were included. In line with this, one F11 haplotype was associated with overall ischemic stroke in the discovery sample and in the replication sample ≤70 years.ConclusionsWe found significant associations between F11 variation and overall ischemic stroke up to 70 years of age. These findings motivate further studies on the role of F11 in ischemic stroke, especially in younger individuals.
Highlights
Coagulation factor XI (FXI) was initially described as a member of the contact activation pathway which, in concert with the factor VII-tissue factor pathway, leads to thrombin generation, and subsequently the formation of a thrombus upon vessel injury
We investigated variation at the F11 locus and ischemic stroke (IS) in the discovery sample Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) with replication in a larger independent sample including participants up to 70 years of age from the Lund Stroke Register (LSR) and Malmö Diet and Cancer study (MDC) studies
We found independent associations between three single single-nucleotide polymorphisms (SNPs) and three haplotypes spanning these SNPs (CAA, CGA, and CGT) and overall IS in the discovery sample SAHLSIS
Summary
Coagulation factor XI (FXI) was initially described as a member of the contact activation pathway which, in concert with the factor VII-tissue factor pathway, leads to thrombin generation, and subsequently the formation of a thrombus upon vessel injury. In studies of younger patients, elevated plasma levels or activity of FXI have been associated with an increased risk of IS, while plasma FXI does not appear to be of equal importance in myocardial infarction [10,11,12,13,14]. These studies provide support for the importance of FXI in thrombosis and, given the mild bleeding phenotype in FXI deficiency, FXI has gained recent attention as a potential target for anticoagulant therapy that could possibly reduce the risk of bleeding [15]. These findings motivate further studies on the role of F11 in ischemic stroke, especially in younger individuals
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