PLoS ONE (Jan 2018)

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 Frossard,
  • Christian 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 Longstreth,
  • 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 Słowik,
  • Tara Stanne,
  • Konstantin Strauch,
  • Turgut Tatlisumak,
  • Vincent N Thijs,
  • Steffen Tiedt,
  • Matthew Traylor,
  • Melanie Waldenberger,
  • Matthew Walters,
  • Wei Zhao,
  • Giorgio Boncoraglio,
  • Stéphanie Debette,
  • Christina Jern,
  • Christopher Levi,
  • Hugh Markus,
  • James Meschia,
  • Arndt Rolfs,
  • Peter Rothwell,
  • Danish Saleheen,
  • Sudha Seshadri,
  • Pankaj Sharma,
  • Cathie Sudlow,
  • Bradford Worrall,
  • METASTROKE Consortium of the ISGC,
  • WTCCC-2 Consortium,
  • O Colin Stine,
  • Steven J Kittner,
  • Braxton D Mitchell

DOI
https://doi.org/10.1371/journal.pone.0206554
Journal volume & issue
Vol. 13, no. 11
p. e0206554

Abstract

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Background and purposePolymorphisms 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.MethodsDiscovery 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-ageResultsAmong 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.ConclusionPROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.