title: ADAMTS genes and the risk of cerebral aneurysm.
abstract: OBJECTIVE Cerebral aneurysms (CAs) affect 2%-5% of the population, and familial predisposition plays a significant role in CA pathogenesis. Several lines of evidence suggest that genetic variations in matrix metalloproteinase genes (MMP) are involved in the etiopathology of CAs. The authors performed a case-control study to investigate the effect of 4 MMP variants from the ADAMTS family on the pathogenesis of CAs. METHODS To identify susceptible genetic variants, the authors investigated 8 single nucleotide polymorphisms (SNPs) in 4 genes from the ADAMTS family (ADAMTS2, -7, -12, and -13) known to be associated with vascular diseases. The study included 353 patients with CAs and 1055 healthy adults. RESULTS The authors found significant associations between CA susceptibility and genetic variations in 3 members of the ADAMTS family. The largest risk for CA (OR 1.32, p = 0.006) was observed in carriers of the ADAMTS2 variant rs11750568, which has been previously associated with pediatric stroke. Three SNPs under investigation are associated with a protective effect in CA pathogenesis (ADAMTS12 variant rs1364044: OR 0.65, p = 0.0001; and ADAMTS13 variants rs739469 and rs4962153: OR 0.77 and 0.63, p = 0.02 and 0.0006, respectively), while 2 other ADAMTS13 variants may confer a significant risk (rs2301612: OR 1.26, p = 0.011; rs2285489: OR 1.24, p = 0.02). CONCLUSIONS These results suggest that reduced integrity of the endothelial wall, as conferred by ADAMTS variants, together with inflammatory processes and defective vascular remodeling plays an important role in CA pathogenesis, although the mechanism of action remains unknown. The authors' findings may lead to specific screening of at-risk populations in the future.
authors.affiliation: Institute of Human Genetics, Genetic Epidemiology;
authors.forename: Astrid
authors.initials: A
authors.lastname: Arning
authors.affiliation: Institute of Neuropathology;
authors.forename: Astrid
authors.initials: A
authors.lastname: Jeibmann
authors.affiliation: Institute of Legal Medicine;
authors.forename: Stephan
authors.initials: S
authors.lastname: Köhnemann
authors.affiliation: Department of Neurosurgery, University Hospital Münster; and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brokinkel
authors.affiliation: Department of Neurosurgery, University Hospital Münster; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Ewelt
authors.affiliation: Institute of Epidemiology and Social Medicine, University of Münster;
authors.forename: Klaus
authors.initials: K
authors.lastname: Berger
authors.affiliation: Institute of Epidemiology and Social Medicine, University of Münster;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wellmann
authors.affiliation: Institute of Clinical Chemistry, Thrombosis and Hemostasis Treatment Center, Kiel, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
authors.affiliation: Department of Neurosurgery, University Hospital Münster; and.
authors.forename: Walter
authors.initials: W
authors.lastname: Stummer
authors.affiliation: Institute of Human Genetics, Genetic Epidemiology;
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.affiliation: Department of Neurosurgery, University Hospital Münster; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Holling
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D008297:Male; D008875:Middle Aged
chemical_list: D000071096:ADAMTS Proteins
keywords: ADAMTS; CA = cerebral aneurysm; FDR = false discovery rate; GWAS = genome-wide association study; HWE = Hardy-Weinberg equilibrium; ICB = intracerebral bleeding; IS = ischemic stroke; MI = myocardial infarction; MMP = matrix metalloproteinase; PS = pediatric stroke; SAB = subarachnoidal bleeding; SNP = single nucleotide polymorphism; TSR = thrombospondin Type 1 sequence repeat motif; cerebral aneurysm; genes; vascular disorders