Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

John W. Cole, Huichun Xu, Kathleen Ryan, Thomas Jaworek, Nicole Dueker, Patrick McArdle, Brady Gaynor, Yu Ching Cheng, Jeffrey O'Connell, Steve Bevan, Rainer Malik, Naveed Uddin Ahmed, Philippe Amouyel, Sheraz Anjum, Joshua C. Bis, David Crosslin, John Danesh, Stefan T. Engelter, Myriam Fornage, Philippe FrossardChristian Gieger, Anne Katrin Giese, Caspar Grond-Ginsbach, Weang Kee Ho, Elizabeth Holliday, Jemma Hopewell, M. Hussain, W. Iqbal, S. Jabeen, Jim Jannes, Ayeesha Kamal, Yoichiro Kamatani, Sandip Kanse, Manja Kloss, Mark Lathrop, Didier Leys, Arne Lindgren, W. T. LongstrethJr, Khalid Mahmood, Christa Meisinger, Tiina M. Metso, Thomas Mosley, Martina Müller-Nurasyid, Bo Norrving, Eugenio Parati, Annette Peters, Alessandro Pezzini, I. Quereshi, Asif Rasheed, A. Rauf, T. Salam, Jess Shen, Agnieszka Slowik, Tara Stanne, Konstantin Strauch, Turgut Tatlisumak, Vincent N. Thijs, Steffen Tiedt, Matthew Traylor, Melanie Waldenberger, Matthew Walters, Wei Zhao, Giorgio Boncoraglio, Stephanie Debette, Christina Jern, Christopher Levi, Hugh Markus, James Meschia, Arndt Rolfs, Peter Rothwell, Danish Saleheen, Sudha Seshadri, Pankaj Sharma, Cathie Sudlow, Bradford Worrall, O. Colin Stine, Steven J. Kittner, Braxton D. Mitchell

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7 Citations (Scopus)


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 multistage 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 (onsetage< 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 additivemodel 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.

Original languageEnglish
Article numbere0206554
JournalPLoS ONE
Issue number11
Publication statusPublished - Nov 2018


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