Several studies, such as the classical twin study which consisted of 15,924 twin pairs have been designed to assess the genetic factors associated with stroke
[6]. Likewise, another twin study provided evidence for genetic factors that may increase the risk of stroke related events, such as death and hospitalization
[7]. This study found greater concordance rates for these associations among monozygotic twins, compared to dizygotic twins
[7]. These two studies were designed long before the human genome project. There could be different environmental effects affecting the results of these studies, which was a major limitation
[8]. Previous studies have reported that first degree relatives are at an increased risk for stroke
[9]. The preponderance of large and small vessel strokes, compared to cardioembolic strokes, is higher among subjects with a family history of stroke
[9]. Sex is an important factor to influence stroke outcome indicating the possible role of the sex chromosome and associated genes; however, recently a review reported no association between sex and stroke
[10]. Similarly, though ethnicity is not widely considered as an important factor affecting acute stroke outcome; it may influence the long-term outcome
[10][11]. A recent study identified that levels of lipoprotein-A were significantly associated with adverse stroke outcomes, and were substantially higher in the Black, compared to the White population
[12]. In addition, hematological disorders are responsible for nearly 1.3% of acute stroke. Some of the common hematological disorders associated with stroke include polycythemia vera, sickle-cell disease, Waldenström macroglobulinemia, multiple myeloma, essential thrombocythemia, thrombotic thrombocytopenic purpura, protein C deficiency, Protein S deficiency, antithrombin deficiency, and Factor V Leiden. A substantial number of these disorders have a genetic predisposition. For example, a large proportion of polycythemia vera patients have a mutation in the exon 14 of the
JAK2 gene (
JAK2V617F), whereas a smaller proportion has mutations in the
JAK2 exon 12
[4].
2.1. Heritability Genes in Stroke (Monogenic and Polygenic Inheritance in Stroke Etiology)
Several animal model studies were conducted to identify potential candidate genes associated with stroke outcome. These studies analyzed the association of single nucleotide polymorphisms (SNPs) in targeted genes. The SNP of COX-2 and rs20417 genes were associated with early neurological deterioration
[13][14]. However, these studies are not supported with further replicational studies and hence warrant further in-depth research. A study reported that several single-gene disorders might influence stroke, such as sickle cell disease, Fabry’s disease, homocystinuria, mitochondrial myopathy, and encephalopathy
[15]. A rare stroke case caused by mutations in the Notch 3 gene (OMIM*600276) showed heritable patterns
[16], which was also reported as a single-gene disorder. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) caused by different types of mutations of Notch 3 gene are associated with extensive cerebral small vessel damage, marked by the accumulation of granular osmiophilic material (GOM)
[17]. Molecular evaluation of the vascular smooth muscles in CADASIL patients showed increased oxidation of soluble guanyl cyclase associated with decreased cyclic GMP levels, which impaired vasorelaxation of the cerebral vasculature
[17]. A number of molecular pathways associated with cell adhesion, extracellular matrix components, misfolding control, autophagy, angiogenesis, and transforming growth factor β (TGFβ) signaling pathway are altered in CADASIL. Metabolic impairment, such as diabetes mellitus further expedites the pathological damage to the cerebral small blood vessels in Notch 3 mutation, resulting in endothelium mitochondrial dysfunction and vascular basement membrane injuries
[18]. This suggests that the heritability of Notch 3 mutation increases the risk for ischemic stroke from small vessel diseases, such as CADASIL (
Table 1).
Table 1. Studies showing stroke related events and clinical or pathological outcomes.
Abbreviations: MZ, monozygotic; DZ, dizygotic; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; GOM, granular osmiophilic material; cGMP, cyclic guanosine monophosphate; PATJ, pals1-associated tight junction; SNP, single nucleotide polymorphism; LDL, low density lipoprotein; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; MCP-1, monocyte chemoattractant protein-1; IL-6, interleukin-6; OGD, oxygen-glucose deprivation; LncRNA, long non-coding RNA; MEG3, maternally expressed gene 3; miR-21/PDAC, micro ribonucleic acid-21/pancreatic ductal adenocarcinoma; SNHG12, small nucleolar RNA host gene 12; miR-199a, micro ribonucleic acid-199a; AMPK, adenosine monophosphate-activated protein kinase.
Heterozygous mutations in the 3ʹuntranslated region (UTR) of the collagen 4A1 encoding gene may also influence ischemic stroke
[19]. A glycine substitution mutation in the triple-helical domains of COL4A1 and COL4A2 may develop neurological and non-neurological manifestations, including hemorrhagic stroke
[20]. The genomic data enables accurate analysis of heterozygous mutations. Another study identified heterozygous mutations in High-Temperature Requirement Serine protease A1 (HTRA1) encoding gene that manifest as stroke and cognitive decline in people aged more than 45 years
[21]. Other mutations were also identified in the HTRA1 gene that may cause cerebral autosomal recessive arteriopathy in younger people who are between 10 to 30 years of age
[22]. Similarly, mutations in adenosine deaminase 2 (ADA2), cathepsin A (CTSA) and forkhead-box C1 (FOXC1) genes were also found to be associated with autosomal dominant small vessel disease
[23][24][25]. In addition, there are several other candidate genes under investigation for a possible association with stroke.
2.2. Multifactorial Stroke and SNPs
It is challenging to identify individual causative mutations in a single gene because many alleles are responsible for minor effects. Therefore, multiple factorial analyses using SNPs were used to gain newer insight by identifying potential genetic risk factors. For example, a study by Mola-Caminal et al. identified a locus located within a candidate gene
[26], which can help in understanding the genetic mechanisms involved in stroke. Newer variants in the gene pals1-associated tight junction (PATJ) were linked to poor functional outcomes at 3-month post-stroke
[26]. rs76221407 was the major SNP variant of the PATJ gene, which was associated with poor outcomes in stroke subjects after 3 months. The locus STRK1 was mapped to identify a susceptible gene for stroke for the first time
[27]. Another study identified a strong association between the phosphodiesterase 4D gene (PDE4D; OMIM 600129*) and two major subtypes of stroke, cardiogenic and carotid stroke. Among 260 PDE4D gene SNPs, six were found to be significantly associated with stroke. Some of the SNPs were from UTR; therefore, these SNPs may affect the transcription of PDE4D
[28]. The 5-lipoxygenase activating protein gene (ALOX5AP; OMIM 603700*) was also associated with an increased risk of stroke
[29]. ALOX5AP SNP haplotypes increase the production of leukotriene B4 in stimulated neutrophils, thereby contributing to vascular inflammation in myocardial infarction and stroke
[29]. The main limitation of studying candidate genes for SNPs and their association with stroke is that they are time consuming and require significant resources
[30][31], and could be associated with false positive results.