Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke
Abstract
Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke.
Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18–59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS.
Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85–0.91) in EOS vs 0.96 (95% CI: 0.92–1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11–1.21) for EOS vs 1.05 (0.99–1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008).
Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
Our analyses revealed 2 variants at the ABO locus that were
highly associated with EOS. These variants tag 2 of the ABO
blood subgroups, O1 and A1, showing a strong deleterious
and protective association with ischemic stroke, respectively.
Non-O blood groups have been associated previously with
risk of ischemic stroke,29-31 but the novel contributions of our
analysis are in showing a significantly stronger association of
these blood groups with EOS compared with LOS and in
linking risk predominantly to the blood subgroup A1. In
particular, our analyses suggest that the ABO blood subgroups
A1-tagging and O1-tagging variants (rs529565 and rs635634)
are sufficient for capturing nearly all of the ABO-mediated
genetic association with early-onset (and perhaps late) stroke.
Stratified analyses indicate that both SNPs are independently
associated with stroke, and further association analyses at the
ABO locus that condition on the effects of these 2 SNPs reveal
only modest additional signal at this locus.
Non-O blood groups have been associated with a variety of
diseases and phenotypes, including arterial and venous
thrombosis.1,20,23,30,32,33 The ABO blood groups are determined
by the ABO gene, and the A and B allele encodes
glycosyltransferase A and B, respectively, whereas the O allele
encodes a nonactive enzyme. The glycosyltransferases
add specific monosaccharides to the precursor H antigen,
producing A and B antigens. These carbohydrate structures
are expressed on red blood cells and on other cell types of
importance for hemostasis, such as platelets and endothelial
cells.34 These carbohydrates are also present on circulating
solubilized glycoproteins, including VWF.34 It is well known
that non-O blood groups have increased plasma levels of
VWF and coagulation factor VIII,20,34-36 with the A1 subtype
having the highest levels of both.37 The ABO locus has also
been shown to associate with circulating levels of other
glycoproteins such as tumor necrosis factor, soluble
E-selection, P-selectin, intracellular adhesion molecule 1,
and thrombomodulin.38,39
Because the ABO locus is so pleiotropic, several mechanisms may
contribute to our finding of an association to EOS. However,
taken together, our results clearly support an increased role of
prothrombotic mechanisms in EOS compared with LOS. First,
we have shown that the ABO rs529565-O1 SNP is not only
associated with EOS but also more strongly associated with early
onset compared with late-onset VTE. Second, our results show
that genetic risk of VTE, a well-recognized prothrombotic
related disorder, is also more strongly associated with EOS
compared with LOS. Consistent with these observations, we
further found that the EOS-associated haplotype colocalizes with
deep venous thrombosis and with increased levels of VWF and
FVIII, which are well-recognized prothrombotic factors.
Although our study had limited power to examine stroke
subtypes, it is notable that the ABO O1 and A1-defining SNPs
were also significantly associated with large artery atherosclerosis,
cardioembolic, and undetermined stroke subtypes.
This leads to the question, what are the clinical implications
of an enrichment of prothrombotic mechanisms in EOS?
Clinical translation will require a better understanding of the
prothrombotic mechanisms in EOS and, likely, a personalized
secondary prevention strategy. The effect sizes of the stroke
associated common variants at the ABO locus are too small
per se to have immediate clinical implications, but gene-gene
and gene-environment interaction deserve future study.40
One path to translation would be to identify gene-drug interactions
(e.g., oral contraceptives and genetic risk for
thrombosis) and determine whether the joint effect has implications
for primary prevention. Additional research implications are that rare
variant studies should target
prothrombotic and related pathways, which could identify
variants of larger effect size.
n.neurology.org/content/neurology/99/16/e1738.full.pdf