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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


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\textgreater/=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\textless60 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.

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