Cole, John W.; Xu, Huichun; Ryan, Kathleen; Jaworek, Thomas; Dueker, Nicole; McArdle, Patrick; Gaynor, Brady; Cheng, Yu-Ching; O'Connell, Jeffrey; Bevan, Steve; Malik, Rainer; Ahmed, Naveed Uddin; Amouyel, Philippe; Anjum, Sheraz; Bis, Joshua C.; Crosslin, David; Danesh, John; Engelter, Stefan T.; Fornage, Myriam; Frossard, Philippe; Gieger, Christian; Giese, Anne-Katrin; Grond-Ginsbach, Caspar; Ho, Weang Kee; Holliday, Elizabeth; Hopewell, Jemma; Hussain, M.; Iqbal, W.; Jabeen, S.; Jannes, Jim; Kamal, Ayeesha; Kamatani, Yoichiro; Kanse, Sandip; Kloss, Manja; Lathrop, Mark; Leys, Didier; Lindgren, Arne; Longstreth, W. T.; Mahmood, Khalid; Meisinger, Christa; Metso, Tiina M.; Mosley, Thomas; Müller-Nurasyid, Martina; Norrving, Bo; Parati, Eugenio; Peters, Annette; Pezzini, Alessandro; Quereshi, I.; Rasheed, Asif; Rauf, A.; Salam, T.; Shen, Jess; Slowik, Agnieszka; Stanne, Tara; Strauch, Konstantin; Tatlisumak, Turgut; Thijs, Vincent N.; Tiedt, Steffen; Traylor, Matthew; Waldenberger, Melanie; Walters, Matthew; Zhao, Wei; Boncoraglio, Giorgio; Debette, Stephanie; Jern, Christina; Levi, Christopher; Markus, Hugh; Meschia, James; Rolfs, Arndt; Rothwell, Peter; Saleheen, Danish; Seshadri, Sudha; Sharma, Pankaj; Sudlow, Cathie; Worrall, Bradford; Stine, O. Colin; Kittner, Steven J.; Mitchell, Braxton D.
(2018):
Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke.
In: PloS one 13(11), e0206554 |
| 779kB |
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<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. 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.
Item Type: | Journal article |
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Faculties: | Medicine |
Subjects: | 600 Technology > 610 Medicine and health |
URN: | urn:nbn:de:bvb:19-epub-59367-7 |
ISSN: | 1932-6203 |
Annotation: | Vollständige Autorenliste s. Volltext (WTCCC-2 Consortium) |
Language: | English |
ID Code: | 59367 |
Deposited On: | 13. Dec 2018 10:39 |
Last Modified: | 04. Nov 2020 13:38 |
- BASE
- Cole, John W.
- Xu, Huichun
- Ryan, Kathleen
- Jaworek, Thomas
- Dueker, Nicole
- McArdle, Patrick
- Gaynor, Brady
- Cheng, Yu-Ching
- O'Connell, Jeffrey
- Bevan, Steve
- Malik, Rainer
- Ahmed, Naveed Uddin
- Amouyel, Philippe
- Anjum, Sheraz
- Bis, Joshua C.
- Crosslin, David
- Danesh, John
- Engelter, Stefan T.
- Fornage, Myriam
- Frossard, Philippe
- Gieger, Christian
- Giese, Anne-Katrin
- Grond-Ginsbach, Caspar
- Ho, Weang Kee
- Holliday, Elizabeth
- Hopewell, Jemma
- Hussain, M.
- Iqbal, W.
- Jabeen, S.
- Jannes, Jim
- Kamal, Ayeesha
- Kamatani, Yoichiro
- Kanse, Sandip
- Kloss, Manja
- Lathrop, Mark
- Leys, Didier
- Lindgren, Arne
- Longstreth, W. T.
- Mahmood, Khalid
- Meisinger, Christa
- Metso, Tiina M.
- Mosley, Thomas
- Müller-Nurasyid, Martina
- Norrving, Bo
- Parati, Eugenio
- Peters, Annette
- Pezzini, Alessandro
- Quereshi, I.
- Rasheed, Asif
- Rauf, A.
- Salam, T.
- Shen, Jess
- Slowik, Agnieszka
- Stanne, Tara
- Strauch, Konstantin
- Tatlisumak, Turgut
- Thijs, Vincent N.
- Tiedt, Steffen
- Traylor, Matthew
- Waldenberger, Melanie
- Walters, Matthew
- Zhao, Wei
- Boncoraglio, Giorgio
- Debette, Stephanie
- Jern, Christina
- Levi, Christopher
- Markus, Hugh
- Meschia, James
- Rolfs, Arndt
- Rothwell, Peter
- Saleheen, Danish
- Seshadri, Sudha
- Sharma, Pankaj
- Sudlow, Cathie
- Worrall, Bradford
- Stine, O. Colin
- Kittner, Steven J.
- Mitchell, Braxton D.
- Google Scholar
- Cole, John W.
- Xu, Huichun
- Ryan, Kathleen
- Jaworek, Thomas
- Dueker, Nicole
- McArdle, Patrick
- Gaynor, Brady
- Cheng, Yu-Ching
- O'Connell, Jeffrey
- Bevan, Steve
- Malik, Rainer
- Ahmed, Naveed Uddin
- Amouyel, Philippe
- Anjum, Sheraz
- Bis, Joshua C.
- Crosslin, David
- Danesh, John
- Engelter, Stefan T.
- Fornage, Myriam
- Frossard, Philippe
- Gieger, Christian
- Giese, Anne-Katrin
- Grond-Ginsbach, Caspar
- Ho, Weang Kee
- Holliday, Elizabeth
- Hopewell, Jemma
- Hussain, M.
- Iqbal, W.
- Jabeen, S.
- Jannes, Jim
- Kamal, Ayeesha
- Kamatani, Yoichiro
- Kanse, Sandip
- Kloss, Manja
- Lathrop, Mark
- Leys, Didier
- Lindgren, Arne
- Longstreth, W. T.
- Mahmood, Khalid
- Meisinger, Christa
- Metso, Tiina M.
- Mosley, Thomas
- Müller-Nurasyid, Martina
- Norrving, Bo
- Parati, Eugenio
- Peters, Annette
- Pezzini, Alessandro
- Quereshi, I.
- Rasheed, Asif
- Rauf, A.
- Salam, T.
- Shen, Jess
- Slowik, Agnieszka
- Stanne, Tara
- Strauch, Konstantin
- Tatlisumak, Turgut
- Thijs, Vincent N.
- Tiedt, Steffen
- Traylor, Matthew
- Waldenberger, Melanie
- Walters, Matthew
- Zhao, Wei
- Boncoraglio, Giorgio
- Debette, Stephanie
- Jern, Christina
- Levi, Christopher
- Markus, Hugh
- Meschia, James
- Rolfs, Arndt
- Rothwell, Peter
- Saleheen, Danish
- Seshadri, Sudha
- Sharma, Pankaj
- Sudlow, Cathie
- Worrall, Bradford
- Stine, O. Colin
- Kittner, Steven J.
- Mitchell, Braxton D.