This study investigated whether 51 putative functional SNPs associated with CHD in multiple antecedent studies predict ischemic stroke among White and Black individuals from the large prospective ARIC study. The motivation for this study comes from the fact that ischemic stroke and CHD may share genetic factors. Three SNPs in Whites and two SNPs in Blacks were associated with incident ischemic stroke, even after taking into account established risk factors. The rs11628722 polymorphism in SERPINA9 was associated with ischemic stroke in both Whites and Blacks from the ARIC study.
Few of the 51 SNPs that had previously been associated with CHD were associated with incident stroke in the ARIC study, and none of them would have been significantly associated with stroke after a simple Bonferroni multiple testing correction for the 51 SNPs tested. These results may be due to the fact that SNPs that confer only modest risk may not replicate in every study, or ischemic stroke and CHD may not have these genetic factors in common. However, it is noteworthy that the association between SERPINA9
and stroke was observed in both Whites and Blacks in this study. This SNP has been associated with myocardial infarction in two case-control studies and this study shows an association with stroke in both Whites and Blacks from the ARIC study. SERPINA9
is a member of clade A of the large superfamily of serine peptidase inhibitors known as serpins. Serpins are protease inhibitors that use a conformational change to inhibit target enzymes, and are involved in many cellular processes, such as coagulation, fibrinolysis, complement fixation, matrix remodeling and apoptosis [15
]. Little is known about the expression of SERPINA9;
however, a recent study indicated that SERPINA9
was significantly upregulated in the hippocampal tissues from Alzheimer's disease transgenic mice versus age-matched controls [16
]. This study suggests that SERPINA9
may also be expressed in the human brain, consistent with our observation of an association between polymorphic variation in this gene and ischemic stroke.
In addition to SERPINA9,
polymorphisms in palladin (PALLD)
and immediate early response 2 (IER2)
were associated with ischemic stroke in Whites and a polymorphism in exonuclease domain containing 1 (EXOD1)
was associated with ischemic stroke in Blacks. PALLD
encodes a component of the cytoskeleton that controls cell shape and motility. Vascular remodeling may lead to atherosclerosis, and the shape and cytoskeletal organization of endothelial cells is an important part of this process. Mechanical stress and strain also plays a role in atherosclerotic vascular remodeling and immediate early response genes have been shown to mediate the mechanical stress-induced pathological process in the blood vessel [17
]. Although little is known about EXOD1,
exonucleases have been shown to play a role in both myocardial infarction and stroke. Given their functional roles, PALLD, IER2
potentially play a role in the atherosclerotic pathway. Additionally, PALLD, IER2
are all expressed in the heart and brain (www.genecards.org
A strength of this study is the prospective cohort design which is ‘valuable for critically examining the potential risk factors that are initially identified through other approaches, including case-control studies’ [18
]. The large sample size allows for the assessment of exposures (e.g. genetic factors) of modest effect. All analyses for this study were performed separately in Whites and Blacks; however, it is important to note that ethnicity in the ARIC study is self-reported and underlying population stratification may be a potential limitation.
In summary, we have identified genes associated with incident ischemic stroke in the ARIC study. In particular, SERPINA9 was associated with stroke in both Whites and Blacks and this association does not appear to be mediated by traditional risk factors. This study underscores the utility of large-scale genomic studies of the occurrence of stroke in humans in order to identify and localize stroke susceptibility genes.