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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-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 (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-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.

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