Format

Send to

Choose Destination
PLoS One. 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.

Author information

1
Veterans Affairs Maryland Health Care System; University of Maryland School of Medicine, Baltimore, MD, United States of America.
2
University of Maryland School of Medicine, Baltimore, MD, United States of America.
3
University of Miami, Miami, Florida, United States of America.
4
Food and Drug Administration, White Oak, MD, United States of America.
5
University of Lincoln, Lincoln, United Kingdom.
6
Klinikum der Universität München, Munich, Germany.
7
Liaquat National Hospital, Karachi, Pakistan.
8
Inserm, Lille, France.
9
Center for Non-Communicable Diseases, Karachi, Pakistan.
10
University of Washington, Seattle, WA, United States of America.
11
University of Cambridge, Cambridge, United Kingdom.
12
University Hospital Basel, Basel, Switzerland.
13
University of Texas Health Science Center at Houston, Houston, TX, United States of America.
14
Helmholtz Zentrum München, München, Germany.
15
Massachusetts General Hospital, Boston, MA, United States of America.
16
Heidelberg University, Heidelberg, Germany.
17
University of Newcastle, Newcastle, Australia.
18
University of Oxford, Oxford, United Kingdom.
19
Lahore General Hospital, Lahore, Pakistan.
20
University of Adelaide, Adelaide, Australia.
21
Aga Khan University Hospital, Karachi, Pakistan.
22
RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
23
Institute of Basic Medical Sciences, Oslo, Norway.
24
McGill University and Québec Innovation Centre, Montreal, Canada.
25
University of Lille; INSERM, Lille, France.
26
Lund University, Lund, Sweden.
27
Harborview Medical Center, Seattle, WA, United States of America.
28
Dow University of Health Sciences, Civil Hospital, Karachi, Pakistan.
29
Central Hospital of Augsburg, Augsburg, Germany.
30
Helsinki University Central Hospital, Helsinki, Finland.
31
University of Mississippi Medical Center, Jackson, MS, United States of America.
32
Institute of Medical Informatics, Ludwig-Maximilians-University, Munich, Germany.
33
Fondazione IRCCS Istituto Neurologico, Milan, Italy.
34
GSF-National Research Center for Environment and Health, Munich, Germany.
35
Universita Degli Studi di Brescia, Brescia, Italy.
36
King Edward Medical University and Mayo Hospital, Lahore, Pakistan.
37
Lunenfeld Tenubaum Research Institute, Toronto, Ontario, Canada.
38
Jagiellonian University Medical College, Krakow, Poland.
39
Institute of Biomedicine, Gothenburg, Sweden.
40
Ludwig-Maximilians University Munich, Munich, Germany.
41
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia.
42
Institute for Stroke and Dementia Research, Ludwig-Maximilians Universität München, Munich, Germany.
43
University of Glasgow, Glasgow, Scotland.
44
Translational Medicine and Human Genetics, Philadelphia, PA, United States of America.
45
Bordeaux University, Bordeaux, France.
46
John Hunter Hospital, New Lambton Heights, NSW, Australia.
47
Mayo Clinic, Jacksonville, FL, United States of America.
48
University of Rostock, Rostock, Mecklenburg-Vorpommern, Germany.
49
John Radcliffe Hospital, Oxford, United Kingdom.
50
University of Pennsylvania, Philadelphia, PA, United States of America.
51
Boston University School of Medicine, Boston, MA, United States of America.
52
Royal Holloway, University of London, London, United Kingdom.
53
University of Edinburgh, Edinburgh, Scotland.
54
University of Virginia, Charlottesville, VA, United States of America.

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.

PMID:
30383853
PMCID:
PMC6211695
DOI:
10.1371/journal.pone.0206554
[Indexed for MEDLINE]
Free PMC Article

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.

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center