Dataset Information

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

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.

SUBMITTER: Cole JW

PROVIDER: S-EPMC6211695 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Cole John W JW Xu Huichun H Ryan Kathleen K Jaworek Thomas T Dueker Nicole N McArdle Patrick P Gaynor Brady B Cheng Yu-Ching YC O'Connell Jeffrey J Bevan Steve S Malik Rainer R Ahmed Naveed Uddin NU Amouyel Philippe P Anjum Sheraz S Bis Joshua C JC Crosslin David D Danesh John J Engelter Stefan T ST Fornage Myriam M Frossard Philippe P Gieger Christian C Giese Anne-Katrin AK Grond-Ginsbach Caspar C Ho Weang Kee WK Holliday Elizabeth E Hopewell Jemma J Hussain M M Iqbal W W Jabeen S S Jannes Jim J Kamal Ayeesha A Kamatani Yoichiro Y Kanse Sandip S Kloss Manja M Lathrop Mark M Leys Didier D Lindgren Arne A Longstreth W T WT Mahmood Khalid K Meisinger Christa C Metso Tiina M TM Mosley Thomas T Müller-Nurasyid Martina M Norrving Bo B Parati Eugenio E Peters Annette A Pezzini Alessandro A Quereshi I I Rasheed Asif A Rauf A A Salam T T Shen Jess J Słowik Agnieszka A Stanne Tara T Strauch Konstantin K Tatlisumak Turgut T Thijs Vincent N VN Tiedt Steffen S Traylor Matthew M Waldenberger Melanie M Walters Matthew M Zhao Wei W Boncoraglio Giorgio G Debette Stéphanie S Jern Christina C Levi Christopher C Markus Hugh H Meschia James J Rolfs Arndt A Rothwell Peter P Saleheen Danish D Seshadri Sudha S Sharma Pankaj P Sudlow Cathie C Worrall Bradford B Stine O Colin OC Kittner Steven J SJ Mitchell Braxton D BD

PloS one 20181101 11

<h4>Background and purpose</h4>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.<h4>Methods</h4>Discovery was performed in the Genetics-of-Early-Onset Stroke ...[more]

PMID: 30383853

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Project description:In a recent meta-analysis migraine was associated with a two-fold increase in stroke risk. While the mechanism driving this association is unknown, one intriguing hypothesis is that migraineurs are genetically predisposed to developing ischemic stroke. Mutations in the ATP1A2 gene are implicated in familial hemiplegic migraine type II and increase the severity of ischemic brain injury in animal models. To further explore these observations, we assessed the association between ATP1A2 polymorphisms, migraine, and the risk of ischemic stroke in participants of the Genetics of Early-Onset Stroke Study, a population-based case-control study of ischemic stroke among men and women aged 15-49. Using responses to a headache symptoms questionnaire, subjects were classified as having no migraine, or migraine with or without visual aura. Evaluating a total of 134 ATP1A2 polymorphisms genotyped using a combination of Illumina platforms (Cardiovascular Gene-centric 50 K SNP Array and HumanOmni1-Quad_v1-0_B Bead Chip), only one polymorphism (rs2070704) demonstrated a nominally significant association with stroke in an age-, gender-, ethnicity-adjusted model (OR?=?0.83, 95% CI?=?0.71-0.98, p?=?0.025) and in a vascular risk factor model adjusting for age, gender, ethnicity, hypertension, diabetes, smoking, and myocardial infarction (OR?=?0.74, 95% CI?=?0.63-0.89, p?=?0.001). Ethnicity-stratified analyses demonstrated a significant association for rs2070704 among African-Americans (OR?=?0.68, 95% CI?=?0.53-0.90, p?=?0.005) but not Caucasians (OR?=?0.82, 95% CI?=?0.64-1.04, p?=?0.107). These associations were unchanged when migraine subtypes were included as co-variates. We did not observe an association between ATP1A2 polymorphisms and migraine. While our results do not demonstrate a strong relationship between ATP1A2 polymorphisms and migraine associated stroke risk, the results are hypothesis generating and indicate that an association between ATP1A2 polymorphisms and stroke risk may exist. Additional studies are required.

Project description:Background and purposeThe genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease.MethodsDiscovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases.ResultsGene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10-6). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10-7), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10-7) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10-6).ConclusionsExome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

Dataset Information

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

Publications

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

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