ADAMTS genes and the risk of cerebral aneurysm

被引:22
作者
Arning, Astrid [1 ]
Jeibmann, Astrid [3 ]
Koehnemann, Stephan [4 ]
Brokinkel, Benjamin [5 ]
Ewelt, Christian [5 ]
Berger, Klaus [2 ]
Wellmann, Juergen [2 ]
Nowak-Goettl, Ulrike [6 ]
Stummer, Walter [5 ]
Stoll, Monika [1 ]
Holling, Markus [5 ]
机构
[1] Univ Munster, Genet Epidemiol, Inst Human Genet, Munster, Germany
[2] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany
[3] Univ Hosp Munster, Inst Neuropathol, Munster, Germany
[4] Univ Hosp Munster, Inst Legal Med, Munster, Germany
[5] Univ Hosp Munster, Dept Neurosurg, Albert Schweitzer Campus 1A, D-48149 Munster, Germany
[6] Univ Hosp Schleswig Holstein, Thrombosis & Hemostasis Treatment Ctr, Inst Clin Chem, Kiel, Germany
关键词
cerebral aneurysm; ADAMTS; genes; vascular disorders; UNRUPTURED INTRACRANIAL ANEURYSMS; GENOME-WIDE ASSOCIATION; SUBARACHNOID HEMORRHAGE; MATRIX METALLOPROTEINASES; INFLAMMATION; GENETICS; STROKE; RUPTURE; POLYMORPHISMS; METAANALYSIS;
D O I
10.3171/2015.7.JNS154
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:269 / 274
页数:6
相关论文
共 47 条
[1]   A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke [J].
Arning, Astrid ;
Hiersche, Milan ;
Witten, Anika ;
Kurlemann, Gerhard ;
Kurnik, Karin ;
Manner, Daniela ;
Stoll, Monika ;
Nowak-Goettl, Ulrike .
BLOOD, 2012, 120 (26) :5231-5236
[2]  
Barrett Jeffrey C, 2009, Cold Spring Harb Protoc, V2009, DOI 10.1101/pdb.ip71
[3]   Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations [J].
Bateman, John F. ;
Boot-Handford, Raymond P. ;
Lamande, Shireen R. .
NATURE REVIEWS GENETICS, 2009, 10 (03) :173-183
[4]   Recommendations for the management of patients with unruptured intracranial aneurysms - A statement for healthcare professionals from the Stroke Council of the American Heart Association [J].
Bederson, JB ;
Awed, IA ;
Wiebers, DO ;
Piepgras, D ;
Haley, EC ;
Brott, T ;
Hademenos, G ;
Chyatte, D ;
Rosenwasser, R ;
Caroselli, C .
STROKE, 2000, 31 (11) :2742-2750
[5]   Biology of intracranial aneurysms: role of inflammation [J].
Chalouhi, Nohra ;
Ali, Muhammad S. ;
Jabbour, Pascal M. ;
Tjoumakaris, Stavropoula I. ;
Gonzalez, L. Fernando ;
Rosenwasser, Robert H. ;
Koch, Walter J. ;
Dumont, Aaron S. .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2012, 32 (09) :1659-1676
[6]   Systemic antithrombotic effects of ADAMTS13 [J].
Chauhan, AK ;
Motto, DG ;
Lamb, CB ;
Bergmeier, W ;
Dockal, M ;
Plaimauer, B ;
Scheiflinger, F ;
Ginsburg, D ;
Wagner, DD .
JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (03) :767-776
[7]   ADAMTS13: a new link between thrombosis and inflammation [J].
Chauhan, Anil K. ;
Kisucka, Janka ;
Brill, Alexander ;
Walsh, Meghan T. ;
Scheiflinger, Friedrich ;
Wagner, Denisa D. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2008, 205 (09) :2065-2074
[8]   Inflammation and intracranial aneurysms [J].
Chyatte, D ;
Bruno, G ;
Desai, S ;
Todor, R .
NEUROSURGERY, 1999, 45 (05) :1137-1146
[9]   Higher sensitivity of Adamts12-deficient mice to tumor growth and angiogenesis [J].
El Hour, M. ;
Moncada-Pazos, A. ;
Blacher, S. ;
Masset, A. ;
Cal, S. ;
Berndt, S. ;
Detilleux, J. ;
Host, L. ;
Obaya, A. J. ;
Maillard, C. ;
Foidart, J. M. ;
Ectors, F. ;
Noel, A. ;
Lopez-Otin, C. .
ONCOGENE, 2010, 29 (20) :3025-3032
[10]   Whole Exome Sequencing of Intracranial Aneurysm [J].
Foroud, Tatiana .
STROKE, 2013, 44 (06) :S26-S28