TY - JOUR
T1 - Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke
AU - Collaborating authors.
AU - Sudlow, Catherine
AU - Xu, Huichun
AU - Ryan, Kathleen
AU - Jaworek, Thomas
AU - Dueker, Nicole
AU - McArdle, Patrick
AU - Gaynor, Brady
AU - Cheng, Yu-Ching
AU - O’connell, Jeffrey R.
AU - Bevan, Steve
AU - Malik, Rainer
AU - Ahmed, Naveed Uddin
AU - Amouyel, Philippe
AU - Anjum, Sheraz
AU - Bis, Joshua C.
AU - Crosslin, David S
AU - Danesh, John
AU - Mitchell, Braxton D.
AU - Kittner, Steven J
AU - Stine, Colin
AU - Worrall, Bradford B
AU - Sharma, Pankaj
AU - Seshadri, Sudha
AU - Engelter, Stefan T
AU - Fornage, Myriam
AU - Frossard, Philippe
AU - Gieger, Christian
AU - Giese, Anne-Katrin
AU - Grond-ginsbach, Caspar
AU - Ho, Weang Kee
AU - Holliday, Elizabeth G.
AU - Rothwell, Peter M. W.
AU - Hopewell, Jemma C.
AU - Hussain, M
AU - Warsi, Iqbal
AU - Jabeen, Sehrish
AU - Jannes, Jim
AU - Kamal, Ayeesha K.
AU - Kamatani, Yoichiro
AU - Kanse, Sandip
AU - Kloss, Manja
AU - Mark Lathrop, G.
AU - Leys, Didier
AU - Lindgren, Arne
AU - Longstreth, W T
AU - Rothwell, Peter M.
AU - Saleheen, Danish
AU - Jern, Christina
AU - Levi, Christopher
AU - Norman, Jane
PY - 2018/11/1
Y1 - 2018/11/1
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0206554
DO - 10.1371/journal.pone.0206554
M3 - Article (Academic Journal)
C2 - 30383853
SN - 1932-6203
VL - 13
JO - PLoS ONE
JF - PLoS ONE
IS - 11
ER -