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

Journal article
Authors 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
O Colin Stine
Steven J Kittner
Braxton D Mitchell
Published in PloS one
Volume 13
Issue 11
ISSN 1932-6203
Publication year 2018
Published at Institute of Biomedicine
Language en
Keywords Adolescent, Adult, African Americans, genetics, Age of Onset, Brain Ischemia, epidemiology, genetics, Case-Control Studies, Endothelial Protein C Receptor, genetics, European Continental Ancestry Group, genetics, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Stroke, epidemiology, genetics, Thrombomodulin, genetics, Young Adult
Subject categories Neurology


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.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.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.PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.

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