Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke.
Cole JW., Xu H., Ryan K., Jaworek T., Dueker N., McArdle P., Gaynor B., Cheng Y-C., O'Connell J., Bevan S., Malik R., Ahmed NU., Amouyel P., Anjum S., Bis JC., Crosslin D., Danesh J., Engelter ST., Fornage M., Frossard P., Gieger C., Giese A-K., Grond-Ginsbach C., Ho WK., Holliday E., Hopewell J., Hussain M., Iqbal W., Jabeen S., Jannes J., Kamal A., Kamatani Y., Kanse S., Kloss M., Lathrop M., Leys D., Lindgren A., Longstreth WT., Mahmood K., Meisinger C., Metso TM., Mosley T., Müller-Nurasyid M., Norrving B., Parati E., Peters A., Pezzini A., Quereshi I., Rasheed A., Rauf A., Salam T., Shen J., Słowik A., Stanne T., Strauch K., Tatlisumak T., Thijs VN., Tiedt S., Traylor M., Waldenberger M., Walters M., Zhao W., Boncoraglio G., Debette S., Jern C., Levi C., Markus H., Meschia J., Rolfs A., Rothwell P., Saleheen D., Seshadri S., Sharma P., Sudlow C., Worrall B., METASTROKE Consortium of the ISGC None., WTCCC-2 Consortium None., Stine OC., Kittner SJ., Mitchell BD.
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.