No evidence for an association between genetic variation at the SERPINI1 locus and ischemic stroke

Neuroserpin, primarily expressed by neurons, is an important inhibitor of tissue-type plasminogen activator (tPA). t-PA has a multifaceted role in the brain and is involved in several physiologic and pathologic processes. Its beneficial role on the vascular side is attributed to its thrombolytic function. Moreover, recombinant t-PA is the only FDA-approved pharmacological treatment of acute ischemic stroke (IS) [1]. In the brain there are several celltypes that express t-PA besides the cerebrovascular endothelial cells, e.g. neurons, microglia and astrocytes [2]. Under physiological conditions t-PA is involved in synaptic plasticity and memory-related processes [3, 4]. However, during pathological conditions, such as in the acute phase of IS, excess release of t-PA may trigger proteolytic cascades, subsequently leading to excitotoxicity and neurodegeneration [5, 6]. In this context, t-PA has been associated with increased stroke volume [7] and increased cerebrovascular permeability [8–10]. Experimental models have also shown that treatment with neuroserpin or neuroserpin gene overexpression results in a reduced infarct volume and prevents t-PA-induced increase in blood–brain barrier permeability [8, 11, 12]. To date, there is only one published study addressing the potential association between common genetic variants at the neuroserpin (SERPINI1) locus and IS. In the Stroke Prevention in Young Women Study 2 (SPYW2), Cole and colleagues detected an association between a single nucleotide polymorphism (SNP) located in intron 1 of the neuroserpin gene (rs6797312) and IS, and this association was restricted to Caucasian women (n = 95) in an ageadjusted dominant model [13]. The aim of the present study was to investigate the association between genetic variants at the SERPINI1 locus and IS in a Swedish sample of relatively young (B70 years) individuals. The study population comprised patients (n = 844) and population-based, healthy controls (n = 668) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), the design of which has been reported [14, 15]. All participants were Caucasian. Patients had presented with first-ever or recurrent acute IS before reaching the age of 70 years. The upper age limit was chosen based on studies indicating that the genetic contribution is greater in patients suffering from stroke at younger age. Written informed consent from participants, and approval by the Ethics Committee of the University of Gothenburg were obtained. Baseline characteristics are presented in Table 1. In addition to rs6797312 [13], 23 haplotype tagging SNPs at the SERPINI1 locus were selected using HapMap (Data release 22/PhaseII on NCBI B36 assembly). Genotyping was performed at the SNP technology platform at Uppsala University (http://genotyping.se) using the Golden Gate assay (Illumina Inc. San Diego, CA, USA). Four of the SNPs (rs2055026, rs1553221, rs13064973, rs1973360) were excluded due to technical difficulties in the assay design and three (rs1192448, rs3792297, rs3792298) were excluded due to low sample call rates (\90%). The average call rate for the SNPs that passed the quality control was 99%. Associations between single SNPs and case/control status were investigated using univariate binary logistic regression primarily adjusted for age and sex. Haplotype analysis was conducted using the software Helix Tree A. Tjarnlund-Wolf S. Olsson K. Jood C. Blomstrand C. Jern (&) Institute of Neuroscience and Physiology, Section for Clinical Neuroscience and Rehabilitation, The Sahlgrenska Academy at University of Gothenburg, Per Dubbsgatan 14, 413 45 Gothenburg, Sweden e-mail: christina.jern@neuro.gu.se