asymmetrical development of the heart and other tissues,^22 and the variant of the
geneZFHX3(zinc finger homeobox 3 or AT-binding transcription factor 1),
encoding for transcription factor that regulates neuronal and myogenic differenti-
ation,^23 both have been initially associated with atrial fibrillation^24 and later have
been identified as independent risk factors for ischemic stroke.^25 Similarly, the
variant of the locus on chromosome 9p2, previously associated with myocardial
infarction,^26 was found to be associated also with ischemic stroke.^27 It would be
very interesting to understand why the common genes are associated with heart and
brain infarcts and to integrate the knowledge about molecular and cellular pathways
involved in their pathology. Namely, both cardiomyocytes and brain and spinal
cord neurons are postmitotic cells that are incapable of proliferation after damage in
postnatal life.^28 Future studies should reveal if the same or similar molecular (for
example, miRNA) networks and modulating molecules could be involved in the
heart and brain regeneration after injury and if same or similar therapeutic strategies
could be involved in repairing the damage after injury.
In 2012, a variant inHDAC9gene encoding histone deacetylase 9 was found by
GWAS to be associated with large-vessel ischemic stroke.^29 It was proposed that
the mechanisms by which variants in HDAC9 increase large artery stroke risk is
through increasing atherogenesis since the therapy with sodium valproate, inhibitor
of HDAC, has been shown to decrease stroke and myocardial infarction rates.^30
In Asiatic populations, GWAS have identified SNP inPRKCH(protein kinase C
eta) gene to be associated with small-vessel stroke,^31 indicating possible involve-
ment of inflammation and atherosclerosis in the development of stroke, since
PRKCH is a serine–threonine kinase mainly expressed in vascular endothelial
cells and foamy macrophages that are essential in all phases of atherosclerosis.^32
For stroke types other than ischemic, GWAS were also performed, showing the
complexity of the approach. Recent GWAS identified two different susceptibility
loci associated with the intracerebral hemorrhage (ICH) stroke subtype, one for
lobar ICH (chromosomal region 12q21.1) and another for nonlobar ICH (chromo-
somal region 1q22), demonstrating once again the correlation between genetic and
pathological heterogeneity of stroke.^33
(^22) Campione et al. ( 1999 ).
(^23) Miura et al. ( 1995 ) and Berry et al. ( 2001 ).
(^24) Damani and Topol ( 2009 ).
(^25) Gretarsdottir et al. ( 2008 ), Gudbjartsson et al. ( 2009 ), and Markus ( 2012 ).
(^26) Helgadottir et al. ( 2007 ).
(^27) Helgadottir et al. ( 2008 ) and Gschwendtner et al. ( 2009 ).
(^28) Mladinic et al. ( 2009 ) and Zacchigna and Giacca ( 2014 ).
(^29) ISGC et al. ( 2012 ).
(^30) Markus ( 2012 ).
(^31) Kubo et al. ( 2007 ) and Wu et al. ( 2009 ).
(^32) Li et al. ( 2012 ).
(^33) Woo et al. ( 2014 ).
246 M.M. Pejatovic ́and S. Anzic ́