Genes involved in risk prediction of Ischemic stroke

Stroke has become a major health problem across the world, they are divided into two main types, ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs as a result of the disturbance in the blood supply to the brain, often due to blockage in one of the arteries that leads to the brain. The underlying condition for this interruption in the development of lipid deposits that line the walls of the blood vessels. This condition is also known as “atherosclerosis.”

Risk factors associated with Ischemic stroke (IS)

Tare many conventional factors associated with ischemic stroke such as high blood pressure, smoking, age, or cardiovascular diseases, however, the risk still remains unexplained. The fact that why some persons with risk factors such as high blood pressure develop stroke while others with almost similar risk remain healthy.

Research in the last couple of decades suggested that genetic factors may be accountable for some of this baffling risk (Markus, 2010). There is a lot of evidence suggesting its monogenic relation. Although, Stroke is also thought to be a complex multifactorial and polygenic disease, that arises from a varied number of gene-environment and gene-gene interactions. Genetic factors might act by predisposing to conventional risk factors, by moderating the effects of those factors on the target tissues, organs or, alternatively, by a direct effect on risk of stroke and on infarct evolution independently (Terni et al., 2015).

Need for identifying genes for stroke

Only a small fraction of ischemic stroke is monogenic. A single mutation in a particular gene can cause disease, and at some stages of life, most of the individuals with the aberration are likely to develop ischemic stroke. For some of these diseases recognizing the underlying mutation permits diagnosis, prognostic information, personalized treatments in a few cases, and it also enables counselling of other family members as well.

On the other hand, large proportions of stroke seem to be “polygenic” i.e. involving multiple genes, with each gene likely to confer a minor risk that interacts with environmental factors to result in ailment. Detecting these genetic factors may allow enhanced risk profiling (Markus, 2010).

Techniques to identify IS-related genes

A linkage is one of the most common techniques used for the identification of genes that causes the monogenic IS. This technique based on recognizing association among chromosomal markers and disease phenotype within the families. Recently the Genome-Wide Association Studies (GWAS) has revolutionized the area of complex-genetics. GWAS allows up to 1,000,000 SNPs (Single Nucleotide Polymorphisms) spanning the entire genome to be genotyped in one individual. By using a case-control approach, and rigorous statistical methods to account for several comparisons made, associations between completely unexpected chromosomal loci and disease can be identified (Markus, 2010).

Monogenic link of ischemic stroke

Around 5% of stroke cases have resulted from the monogenic disorders (it may be underestimated), over 50 monogenic disorders are associated with ischemic stroke. The disease is mainly categorized as a Mendelian disorder and the mitochondrial disorder. Mendelian disease can be identified by severe clinical course, familial aggregation, early onset, high rate of occurrence. Fabry disease is an example of Mendelian disorder, it is an X-linked lysosomal storage disorder and is congenital, it occurs due to an incomplete or complete deficit of α-galactosidase-A enzyme, which plays an important role in the breakdown of glycolipids and glycoprotein.

Lack of this enzyme can cause the accumulation of a high level of fatty lipids and proteins. On the other hand, mitochondrial-associated stroke can be inherited maternally, often multi-systemic and it could be life-threatening. MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode) is an excellent example of mitochondrial-associated stroke, it is maternally inherited and it is caused due to a number of various point mutations. In table 1 some of the common genes associated with stroke and their functions are mentioned.

S.No

Disease

Genes involved

Function

References

1. MELAS tRNA (Leu) A3243G Mitochondrial tRNA (Goto et al., 1992)
2. Small vessel disease COL4A1 Encoding α1[V1]-chain of collagen type IV (Federico et al., 2012)
3. Stroke and vasculopathy with ADA2 mutations CECR1 Transcription of ADA2 protein (Zhou et al., 2014)
4. FABRY α-GAL A Encodes α-galactosidase A enzyme (Federico et al., 2012)
5. HERNS TREX1 Encodes 3’-prime repair exonuclease 1 (Federico et al., 2012)
6. Sickle cell disease Hemoglobin β-chain gene Encodes for β-chain of normal hemoglobin (Razvi and Bone, 2006)
7. Homocystinuria Multiple genes encoding various enzymes Deficiencies of these enzymes can cause very high plasma concentrations of homocysteine and homocystinuria (Dichgans, 2007)

Table: List of some common monogenic genes related to IS

A polygenic connection of ischemic stroke

Only marginal cases of stroke are linked to single-gene disorders (monogenic). However, a large proportion of stroke cases are associated with polygenic conditions. It represents a complex situation, where multiple genes and various environmental factors are involved. In this set-up, the role of an abundant number of contender genes has been studied through association studies, with provocative results (table). In polyfactorial and polygenic disorders, both several genetic and environmental factors are obligatory to reach a level of threshold, which is necessary for the manifestation of phenotype (Terni et al., 2015).

S.No

Polymorphism

Genes involved

Function

References

1. C677T MTHFR Associated with high levels of plasmatic homocysteine (Casas et al., 2005)
2. IID situated at intron 16 ACE Crucial for renin-angiotensin aldosterone system (Tuncer et al., 2006)
3. M235T AGT Glycoprotein substrate for the action of renin (Van Rijn et al., 2007)
4. c.20210G4A Prothrombin gene Associated with a heightened level of prothrombin (Poort et al., 1996)
5. 4GI5G PAI-1 (SERPINE1) PAI-1 is a fast-acting inhibitor of tissue plasminogen, which plays a key role in fibrinolytic homeostasis (Reiner, Siscovick and Rosendaal, 2001)
6. APOE ε2/ε3/ε4 It may have a role in the levels of total cholesterol, apoE plasma and LDL level (CL et al., 2007)
7. c.455G4A Fibrinogen gene Possible association between fibrinogen polymorphisms, high fibrinogen levels and arterial thrombosis (Bersano et al., 2008)
8. c.1691G4A FV This mutation leads to a p.Arg506Gln amino- acid change, which determines a resistance to PCR (activated protein C), a stroke predisposing condition (Bersano et al., 2008)

Table: list of some common polygenic genes related to IS

In conclusion, genetic factors seem to be a crucial factor in the development of ischemic stroke. Detecting these genetic factors may also allow enhanced risk profiling. Findings in the genetics of ischemic stroke are still not as reliable, therefore, there is a great need for further research in this field to validate the results. Finally, genes for stroke can be cast-off as targets for the development of new drugs that might useful for both prevention & treatment of stroke.

References

  • Bersano, A. et al. (2008) ‘Genetic polymorphisms for the study of multifactorial stroke’, Human Mutation, pp. 776–795. doi: 10.1002/humu.20666.
  • Casas, J. P. et al. (2005) ‘Homocysteine and stroke: Evidence on a causal link from mendelian randomisation’, Lancet, 365(9455), pp. 224–232. doi: 10.1016/S0140-6736(05)70152-5.
  • CL, L. et al. (2007) ‘Association of apolipoprotein E polymorphism with ischemic stroke subtypes in Taiwan.’, Kaohsiung J Med Sci, 23(10), pp. 491–497. Available at: http://pesquisa.bvsalud.org/portal/resource/en/mdl-18055294.
  • Dichgans, M. (2007) ‘Genetics of ischaemic stroke’, Lancet Neurol, 6(2), pp. 149–161. doi: 10.1016/S1474-4422(07)70028-5.
  • Federico, A. et al. (2012) ‘Hereditary cerebral small vessel diseases: A review’, Journal of the Neurological Sciences, 322(1–2), pp. 25–30. doi: 10.1016/j.jns.2012.07.041.
  • Goto, Y. et al. (1992) ‘Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation.’, Neurology, 42(3 Pt 1), pp. 545–50. doi: 10.1212/WNL.42.3.545.
  • Markus, H. S. (2010) ‘Unravelling the genetics of Ischaemic stroke’, PLoS Medicine, 7(3), pp. 1–5. doi: 10.1371/journal.pmed.1000225.
  • Poort, S. R. et al. (1996) ‘A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.’, Blood, 88(10), pp. 3698–703. doi: 10.1001/jama.285.19.2486.
  • Razvi, S. S. M. and Bone, I. (2006) ‘Single gene disorders causing ischaemic stroke’, Journal of Neurology, pp. 685–700. doi: 10.1007/s00415-006-0048-8.
  • Reiner, A. P., Siscovick, D. S. and Rosendaal, F. R. (2001) ‘Platelet glycoprotein gene polymorphisms and risk of thrombosis: facts and fancies’, Rev Clin Exp Hematol, 5(3), p. 262.
  • Van Rijn, M. J. E. et al. (2007) ‘Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes’, Journal of Hypertension, 25(3), pp. 565–570. doi: 10.1097/HJH.0b013e32801449fb.
  • Terni, E. et al. (2015) ‘Genetics of ischaemic stroke in young adults’, BBA Clinical, pp. 96–106. doi: 10.1016/j.bbacli.2014.12.004.
  • Tuncer, N. et al. (2006) ‘Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke’, Journal of Clinical Neuroscience, 13(2), pp. 224–227. doi: 10.1016/j.jocn.2005.08.005.
  • Zhou, Q. et al. (2014) ‘Early-Onset Stroke and Vasculopathy Associated with Mutations in ADA2’, New England Journal of Medicine, 370(10), pp. 911–920. doi: 10.1056/NEJMoa1307361.

Avishek Majumder

Research Analyst at Project Guru
Avishek is a Master in Biotechnology and has previously worked with Lifecell International Private Limited. Apart from data analysis and biological research, he loves photography and reading. He loves to play football and basketball in his spare time with an avid interest in adventure and nature. He was also a member of the Scouts in his school and has attended Military training.
Avishek Majumder

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