학술논문
Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke.
Document Type
article
Author
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
Source
PLoS ONE, Vol 13, Iss 11, p e0206554 (2018)
Subject
Language
English
ISSN
1932-6203
Abstract
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.