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

PLoS One. 2018 Nov 1;13(11):e0206554. doi: 10.1371/journal.pone.0206554. eCollection 2018.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • African Americans / genetics
  • Age of Onset
  • Brain Ischemia / epidemiology
  • Brain Ischemia / genetics*
  • Case-Control Studies
  • Endothelial Protein C Receptor / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Stroke / epidemiology
  • Stroke / genetics*
  • Thrombomodulin / genetics*
  • Young Adult

Substances

  • Endothelial Protein C Receptor
  • PROCR protein, human
  • THBD protein, human
  • Thrombomodulin

Associated data

  • ISRCTN/ISRCTN48489393