1. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke
- Author
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Cole, J, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y, O'Connell, J, Bevan, S, Malik, R, Ahmed, N, Amouyel, P, Anjum, S, Bis, J, Crosslin, D, Danesh, J, Engelter, S, Fornage, M, Frossard, P, Gieger, C, Giese, A, Grond-Ginsbach, C, Ho, W, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, W, Mahmood, K, Meisinger, C, Metso, T, Mosley, T, Müller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Słowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, V, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Isgc, Metastroke Consortium Of The, Consortium, Wtccc-2, Stine, O, Kittner, S, Mitchell, B, Cole, John W [0000-0001-9263-8930], Gaynor, Brady [0000-0002-4142-0613], Pezzini, Alessandro [0000-0001-8629-3315], Thijs, Vincent N [0000-0002-6614-8417], Apollo - University of Cambridge Repository, Faculty of Medicine, Neurologian yksikkö, Clinicum, Department of Neurosciences, HUS Neurocenter, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Oncology ,Male ,Thrombomodulin ,Social Sciences ,Genome-wide association study ,030204 cardiovascular system & hematology ,Cardiovascular Medicine ,Vascular Medicine ,3124 Neurology and psychiatry ,Brain Ischemia ,Brain ischemia ,0302 clinical medicine ,Sociology ,Consortia ,YOUNG-ADULTS ,Medicine and Health Sciences ,Medicine ,FACTOR-V-LEIDEN ,Ethnicities ,Age of Onset ,African American people ,POPULATION ,education.field_of_study ,Endothelial protein C receptor ,Multidisciplinary ,Endothelial Protein C Receptor ,Genomics ,Middle Aged ,Population groupings ,3. Good health ,Stroke ,Hemorrhagic Stroke ,VINTAGE ,Neurology ,Cardiovascular Diseases ,Female ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Science ,Cerebrovascular Diseases ,Population ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,CLASSIFICATION ,White People ,MECHANISMS ,Molecular Genetics ,03 medical and health sciences ,Young Adult ,Internal medicine ,Factor V Leiden ,Genome-Wide Association Studies ,Genetics ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,GENOME-WIDE ASSOCIATION ,education ,Molecular Biology ,POLYMORPHISMS ,METAANALYSIS ,Genetic Association Studies ,Ischemic Stroke ,business.industry ,MORTALITY ,Case-control study ,3112 Neurosciences ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,medicine.disease ,Genome Analysis ,Black or African American ,MYOCARDIAL-INFARCTION ,Case-Control Studies ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,3111 Biomedicine ,Age of onset ,People and places ,business ,030217 neurology & neurosurgery - Abstract
Background and purpose Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin−protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. Methods Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15–49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age Results Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. Conclusion PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.
- Published
- 2018
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