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In the last decade, extracranial spontaneous cervical artery dissection (sCAD) became increasingly recognised as a common cause of juvenile stroke. Hereditary connective tissue diseases such as Ehlers-Danlos syndrome type IV (EDS IV) and Marfan syndrome can be associated with sCAD and clinical signs of mild connective tissue weakness have been described in some patients with sCAD.1 Brandt and co-workers found connective tissue aberrations mainly affecting the collagen fibres in skin biopsies of approximately 60% of patients with sCAD.2 Similar skin aberrations were found in patients with intracranial aneurysms (IA).3 A familial association of IA and sCAD has been observed in a few families.4 These findings suggest that connective tissue abnormalities are common to both diseases and might predispose to IA as well as to sCAD. Recently, association between the functional coding single nucleotide polymorphism (SNP) rs42524 in the collagen 1A2 (COL1A2) gene and IA has been described.5 The SNP rs42524 causes a base change G1645C and an amino acid change alanine 549 to proline in the COL1A2 gene (cDNA NM_000089).
In this study we test the hypothesis that the SNP rs42524 is also associated with sCAD. We studied 144 unrelated patients with extracranial sCAD (86 men, mean age 47.4 (standard deviation (SD) 11.5) years; 89 sCAD of the internal carotid artery (ICA), 49 of the vertebral artery (VA), and 6 of the ICA and the VA; patients without known specification of the dissected artery were excluded) and 162 healthy age and sex matched blood donors (98 men, mean age 43.5 (SD 8.7) years) from the province of North Rhine-Westfalia, Germany. All patients were enrolled retrospectively by the Department of Neurology of the University of Münster (described in Konrad et al6) and the Department of Neurology of the Alfried Krupp Hospital, Essen in essentially the same way. The diagnosis of sCAD required clinical symptoms suggestive of sCAD and either evidence of intramural haematoma on MRI examination of the cervical arteries with transverse sections through the neck or typical signs of sCAD on intra-arterial digital subtraction angiography. Subjects gave informed consent and the study was approved by the local ethics committee. Genomic DNA was extracted from peripheral blood lymphocytes. Genotyping was performed using a PCR-RFLP assay. Genotype and allele differences between groups were assessed using χ2 statistics. Hardy-Weinberg equilibrium was calculated using an online resource (http://kursus.kvl.dk/shares/vetgen). Probability (p) values of less than 0.05 were considered statistically significant. The study had 84% power to detect an association with an OR of 3.19 described in familial Japanese IA and 58% to detect an association with an OR of 1.99 described in sporadic Japanese IA with 95% confidence (PS program; http://statgen.iop.kcl.ac.uk/gpc/). The genotype and allele frequencies of the SNP rs42524 are shown in table 1. Genotype frequencies in the patients, as well as in the control group, were in good agreement with Hardy-Weinberg equilibrium (p = 0.49 for controls and p = 0.47 for patients). Neither genotype nor allele frequencies showed significant differences between sCAD patients and controls in the whole sample, after stratification for the affected vessel (ICA or VA) (table 1) or after stratification for gender (results not shown).
The COL1A2 gene is located on chromosome 7q22.1, a chromosomal region showing linkage with IA.7 The SNP rs42524 in the COL1A2 gene showed strong association with IA in a Japanese IA cohort and supposedly influences the thermal stability of collagen.5 We investigated this SNP in sCAD patients because of the presumed pathophysiological similarities between both diseases. We did not find an association between sCAD and the SNP rs42524. However, it can not be excluded that this is due to ethnically determined differences in allele frequencies, because the chromosome 7q locus for IA as well as the association with the SNP rs42524 were originally found in a Japanese sample in which the C allele has a frequency of only 2.7% in the control group, while we studied a Caucasian population in which the C allele had a frequency of 23%.5 The sample size of the Japanese study (260 IA patients) and of our own study (144 sCAD) were of the same order of magnitude. In summary, this study renders it unlikely that the SNP rs42524 plays a major role in the pathogenesis of sCAD in Caucasians. However, this study does not exclude the possibility that other polymorphisms in the COL1A2 gene, which is a very large gene covering 37 000 bp of genomic DNA, are associated with sCAD.
The research reported in this manuscript has partly been sponsored by the Bundesministerium für Bildung und Forschung (BMBF) within the stroke competence network
Competing interests: none declared