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. 2018 Nov 1;13(11):e0206554.
doi: 10.1371/journal.pone.0206554. eCollection 2018.

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

John W Cole  1 , Huichun Xu  2 , Kathleen Ryan  2 , Thomas Jaworek  2 , Nicole Dueker  3 , Patrick McArdle  2 , Brady Gaynor  2 , Yu-Ching Cheng  4 , Jeffrey O'Connell  2 , Steve Bevan  5 , Rainer Malik  6 , Naveed Uddin Ahmed  7 , Philippe Amouyel  8 , Sheraz Anjum  9 , Joshua C Bis  10 , David Crosslin  10 , John Danesh  11 , Stefan T Engelter  12 , Myriam Fornage  13 , Philippe Frossard  9 , Christian Gieger  14 , Anne-Katrin Giese  15 , Caspar Grond-Ginsbach  16 , Weang Kee Ho  11 , Elizabeth Holliday  17 , Jemma Hopewell  18 , M Hussain  9 , W Iqbal  19 , S Jabeen  9 , Jim Jannes  20 , Ayeesha Kamal  21 , Yoichiro Kamatani  22 , Sandip Kanse  23 , Manja Kloss  16 , Mark Lathrop  24 , Didier Leys  25 , Arne Lindgren  26 , W T Longstreth Jr  27 , Khalid Mahmood  28 , Christa Meisinger  29 , Tiina M Metso  30 , Thomas Mosley Jr  31 , Martina Müller-Nurasyid  32 , Bo Norrving  26 , Eugenio Parati  33 , Annette Peters  34 , Alessandro Pezzini  35 , I Quereshi  36 , Asif Rasheed  9 , A Rauf  9 , T Salam  19 , Jess Shen  37 , Agnieszka Słowik  38 , Tara Stanne  39 , Konstantin Strauch  40 , Turgut Tatlisumak  30 , Vincent N Thijs  41 , Steffen Tiedt  42 , Matthew Traylor  11 , Melanie Waldenberger  14 , Matthew Walters  43 , Wei Zhao  44 , Giorgio Boncoraglio  33 , Stéphanie Debette  45 , Christina Jern  39 , Christopher Levi  46 , Hugh Markus  11 , James Meschia  47 , Arndt Rolfs  48 , Peter Rothwell  49 , Danish Saleheen  50 , Sudha Seshadri  51 , Pankaj Sharma  52 , Cathie Sudlow  53 , Bradford Worrall  54 ; METASTROKE Consortium of the ISGC; WTCCC-2 Consortium; O Colin Stine  2 , Steven J Kittner  1 , Braxton D Mitchell  2
Affiliations

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

John W Cole et al. PLoS One. .

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.

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Conflict of interest statement

Drs. Cole, Mitchell, Kittner, Longstreth, and Worrall are supported by research grants from National Institutes of Health (NIH). Dr Cole is supported by a research grants from the American Heart Association and Bayer Pharmaceuticals. Dr. Worrall is Deputy Editor for AAN/Neurology. Dr. Boncoraglio is supported by a research grant from the Fondazione IRCCS Istituto Neurologico Carlo Besta. Dr. Metso is supported by grants from the Finnish Medical Foundation, the Orion Farmos Research Foundation, the Maud Kuistila Memorial Foundation, and the Emil Aaltonen Foundation. Dr. Danesh serves on advisory boards for Novartis, Merck Sharp & Dohme UK, Sanofi, the Medical Research Council, and Wellcome Trust and is a consultant for Takeda. These do not alter the authors adherence to PLOS ONE policies on sharing data and materials. The other authors report no disclosures.

Figures

Fig 1
Fig 1. The thrombomodulin−protein C receptor (TM-EPCR) system located on the endothelial surface.
See this image and copyright information in PMC

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