Journal
PLOS ONE
Volume 13, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0206554
Keywords
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Categories
Funding
- Epidemiology of Aging Training Program Grant, NIH/NIA [T32 AG000262]
- U.S. Department of Veterans Affairs
- American Heart Association Cardiovascular Genome-Phenome Study [15GPSPG23770000]
- American Heart Association Discovery Grant - Bayer Group [17IBDG33700328]
- National Institutes of Health Genes, Environment and Health Initiative (GEI), as part of the GENEVA consortium under GEI [U01 HG004436]
- Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]
- Office of Research and Development, Medical Research Service
- Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs
- National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS069208]
- NIH Office of Research on Women's Health [R01 NS45012, U01 NS069208-01]
- Australian National and Medical Health Research Council (NHMRC) [569257]
- Australian National Heart Foundation (NHF) [G 04S 1623]
- University of Newcastle
- National Heart Foundation
- National Stroke Foundation of Australia [100071]
- Department of Health (UK)
- Henry Smith Charity
- UK-India Education Research Institutive (UKIERI) from the British Council
- UK Medical Research Council (MRC) [ISRCTN48489393]
- British Heart Foundation [ISRCTN48489393]
- Roche Vitamins Ltd [ISRCTN48489393]
- Merck and Co.
- Intramural Research Program of the NIA, NIH [Z01 AG-000015-50]
- American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]
- National Center for Research Resources [U54 RR020278]
- Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8, GR-2011-02347041]
- Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]
- Stroke Association
- National Institute of Health Research (NIHR)
- NIHR Biomedical Research Centre, Oxford
- Binks Trust
- Chief Scientist Office
- Vascular Dementia Research Foundation
- BHF Centre of Research Excellence in Oxford
- United States National Human Genome Research Institute (NHGRI), as part of the Genomics and Randomized Trials Network (GARNET) [U01 HG005160]
- United States National Center for Biotechnology Information
- NHGRI GARNET [U01 HG005152]
- NIH Genes, Environment, and Health Initiative (GEI) [U01 HG004424]
- National Institutes of Health (NIH) [U01 NS069208, HHSN268200782096C, R01 NS100178, R01 NS105150, U01 HG005157, R01 NS34447]
- University of Maryland School of Medicine
- German Federal Ministry of Education and Research (BMBF)
- FP7 European Union project CVgenes@target [261123]
- DFG [CRC 1123]
- Corona Foundation
- Fondation Leducq
- Division of Adult and Community Health, Centers for Disease Control
- Gladys M Brawn Fellowship scheme
- Vincent Fairfax Family Foundation in Australia
- Merck and Co [ISRCTN48489393]
- British Heart Foundation
- NIH-NINDS [R01 NS-42733, R01 NS-39987]
- NIH and NHLBI's STAMPEED genomics research program [R01 HL087676]
- MRC
- Dunhill Medical Trust
- Scottish Funding Council
- Wellcome Trust [090532/Z/09/Z]
- United States Public Health Service, NINDS, Bethesda, Maryland [R01 NS34447]
- US National Library of Medicine
- MRC [MR/L003120/1] Funding Source: UKRI
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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-tage 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 1549 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 (r(2)>= 0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-ge<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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