Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke
<strong>Background and purpose</strong> 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 si...
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| Materyal Türü: | Journal article |
| Dil: | English |
| Baskı/Yayın Bilgisi: |
Public Library of Science
2018
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| _version_ | 1826256425208250368 |
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| author | 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 Metastroke Consortium Of The Isgc, Wtccc-2 Consortium, Stine, O Kittner, S Mitchell, B |
| author_facet | 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 Metastroke Consortium Of The Isgc, Wtccc-2 Consortium, Stine, O Kittner, S Mitchell, B |
| author_sort | Cole, J |
| collection | OXFORD |
| description | <strong>Background and purpose</strong> 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. <br/><br/> <strong>Methods</strong> 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<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case–control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. <br/><br/> <strong>Results</strong> 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. <br/><br/> <strong>Conclusion</strong> PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians. |
| first_indexed | 2024-03-06T18:02:04Z |
| format | Journal article |
| id | oxford-uuid:001e474a-957b-43fa-a363-3b9577845dba |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:02:04Z |
| publishDate | 2018 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:001e474a-957b-43fa-a363-3b9577845dba2022-03-26T08:28:04ZGenetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic strokeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:001e474a-957b-43fa-a363-3b9577845dbaEnglishSymplectic Elements at OxfordPublic Library of Science2018Cole, JXu, HRyan, KJaworek, TDueker, NMcArdle, PGaynor, BCheng, YO'Connell, JBevan, SMalik, RAhmed, NAmouyel, PAnjum, SBis, JCrosslin, DDanesh, JEngelter, SFornage, MFrossard, PGieger, CGiese, AGrond-Ginsbach, CHo, WHolliday, EHopewell, JHussain, MIqbal, WJabeen, SJannes, JKamal, AKamatani, YKanse, SKloss, MLathrop, MLeys, DLindgren, ALongstreth, WMahmood, KMeisinger, CMetso, TMosley, TMüller-Nurasyid, MNorrving, BParati, EPeters, APezzini, AQuereshi, IRasheed, ARauf, ASalam, TShen, JSłowik, AStanne, TStrauch, KTatlisumak, TThijs, VTiedt, STraylor, MWaldenberger, MWalters, MZhao, WBoncoraglio, GDebette, SJern, CLevi, CMarkus, HMeschia, JRolfs, ARothwell, PSaleheen, DSeshadri, SSharma, PSudlow, CWorrall, BMetastroke Consortium Of The Isgc,Wtccc-2 Consortium,Stine, OKittner, SMitchell, B<strong>Background and purpose</strong> 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. <br/><br/> <strong>Methods</strong> 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<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case–control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. <br/><br/> <strong>Results</strong> 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. <br/><br/> <strong>Conclusion</strong> PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians. |
| spellingShingle | 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 Metastroke Consortium Of The Isgc, Wtccc-2 Consortium, Stine, O Kittner, S Mitchell, B Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke |
| title | Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke |
| title_full | Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke |
| title_fullStr | Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke |
| title_full_unstemmed | Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke |
| title_short | Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke |
| title_sort | genetics of the thrombomodulin endothelial cell protein c receptor system and the risk of early onset ischemic stroke |
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