Dr. Sumeet K., PhD
Stroke is a serious medical condition that affects millions of people worldwide. It is a leading cause of disability and death, and its incidence is on the rise.
While many risk factors for stroke have been identified, including high blood pressure, smoking, and diabetes, recent research has shown that genetics may also play a significant role in determining an individual’s risk of stroke.
Studies have shown that certain genetic variations can increase an individual’s risk of stroke. For example, a variant of the F5 gene has been associated with an increased risk of ischemic stroke, while variations in the APOE gene have been linked to an increased risk of hemorrhagic stroke.
Additionally, genetic factors may interact with other risk factors, such as smoking or high blood pressure, to further increase an individual’s risk of stroke.
Understanding the role of genetics in stroke risk is an important area of research, as it may help identify individuals who are at high risk of stroke and allow for earlier interventions to prevent stroke from occurring.
In this article, we will explore the current state of research on genetics and stroke risk, including the latest findings on genetic risk factors and their interactions with other risk factors.
Key Takeaways
- Genetics significantly influences stroke risk, alongside lifestyle and environmental factors.
- Specific genes like F5, APOE, MTHFR, PITX2, and ZFHX3 are linked to increased stroke risk.
- Genetic variants interact with lifestyle factors (e.g., smoking, hypertension) to impact stroke risk.
- Different strokes (ischemic, hemorrhagic, TIAs) have distinct genetic risk factors.
- Hereditary syndromes (CADASIL, CARASIL, MELAS) show the direct impact of genetics on stroke risk.
- Advances in genetic research, including GWAS and polygenic risk scores, improve stroke risk prediction.
Different Types of Strokes and Role of Genetics
Strokes are medical conditions that occur when the blood supply to part of the brain is interrupted or reduced, preventing brain tissue from getting oxygen and nutrients. Brain cells begin to die in minutes.
Strokes can be classified into three main types: ischemic, hemorrhagic, and transient ischemic attacks (TIAs).
The role of genetics in these conditions varies, influencing both susceptibility and the interplay with other risk factors.
1. Ischemic Stroke
Ischemic strokes are the most common type, accounting for about 85% of all strokes. They occur when arteries to your brain become narrowed or blocked, causing severely reduced blood flow (ischemia).
The blockages are often caused by blood clots, which can form either in the brain’s blood vessels (thrombotic stroke) or elsewhere in the body and travel to the brain (embolic stroke).
Genetics plays a significant role in ischemic stroke risk. Variants in genes such as F5, which is linked to blood clotting, and MTHFR, which influences homocysteine levels in the body, can increase the risk.
Additionally, genetic predispositions to conditions like atrial fibrillation (influenced by genes like PITX2 and ZFHX3) can heighten the risk of embolic stroke due to irregular heart rhythms leading to clot formation.
2. Hemorrhagic Stroke
Hemorrhagic strokes result from a blood vessel rupturing and bleeding into the brain.
This category includes intracerebral hemorrhages, where the bleeding occurs within the brain tissue, and subarachnoid hemorrhages, where bleeding occurs between the brain and the surrounding membrane.
High blood pressure and aneurysms (weak and bulging sections of blood vessel walls) are common causes.
Genetic factors also contribute to hemorrhagic stroke risk, particularly through their influence on blood vessel integrity and blood pressure regulation.
Variants in the APOE gene, for example, are associated with an increased risk of cerebral amyloid angiopathy, a condition that can lead to intracerebral hemorrhages.
Additionally, genetic predispositions to hypertension can indirectly increase the risk of hemorrhagic stroke.
3. Transient Ischemic Attacks (TIAs)
Often called mini-strokes, TIAs are brief episodes of stroke-like symptoms but do not cause lasting damage.
They occur when there is a temporary decrease in blood supply to part of the brain, which can last as little as a few minutes.
TIAs should be taken very seriously, as they can be predictors of a future stroke.
While less is known about the specific genetic factors influencing TIAs, the genetic predispositions that increase the risk of ischemic strokes also contribute to TIAs.
This is due to the similar mechanisms of reduced blood flow and the potential for blood clots to temporarily block blood vessels in the brain.
Since these genetic risk factors are inherited, it becomes crucial for individuals with a family history of stroke to be aware of their increased risk and manage other modifiable risk factors to minimize their overall stroke risk.
Genetics and Stroke Risk
Stroke is a complex and multifactorial disease caused by the combination of vascular risk factors, environment, and genetic factors.
Investigations of the genetics of stroke have identified several genetic risk factors that contribute to the development of ischemic and hemorrhagic stroke.
Common Genetic Variants
GWAS Findings
Genome-wide association studies (GWAS) have identified several genetic variants associated with an increased risk of stroke. One such variant is the 9p21 locus, which has been found to be associated with an increased risk of ischemic stroke.
Another study published in Circulation Research found that several common variants or genetic polymorphisms are associated with stroke risk, although the effect size of individual variants is relatively small.
Another study published in PGS Journal found that genetic variants in coagulation factor XIII B-subunit contribute to the risk of ischemic stroke.
The International Stroke Genetics Consortium has identified several genetic variations that may influence stroke risk.
These include variations in genes involved in blood pressure regulation, coagulation, and lipid metabolism. Other genetic variations associated with stroke risk include those involved in inflammation, oxidative stress, and endothelial function.
Polygenic Risk Scores
Polygenic risk scores (PRS) are a tool used to estimate an individual’s genetic risk for a particular disease or condition.
PRS are calculated by combining information from multiple genetic variants associated with the disease or condition. Recent studies have shown that PRS can be used to predict an individual’s risk of stroke with high accuracy.
For example, a study published in the Journal of the American Heart Association found that a PRS based on 90 genetic variants was able to predict stroke risk in a large cohort of individuals of European ancestry.
Specific Genes Known to Influence Stroke Risk
Delving deeper, research has found additional genes beyond F5 and APOE that are implicated in stroke risk.
For instance, the MTHFR gene, associated with homocysteine metabolism, has been linked to stroke risk, particularly when combined with lifestyle factors like diet.
The PITX2 and ZFHX3 genes, associated with atrial fibrillation, also contribute to stroke risk, highlighting the genetic diversity underlying this condition.
Hereditary Stroke Syndromes
Some types of stroke are caused by genetic mutations that run in families. These hereditary stroke syndromes can result in strokes occurring at a younger age and with greater frequency than in the general population.
There are three primary hereditary stroke syndromes: CADASIL, CARASIL, and MELAS.
CADASIL
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary stroke syndrome that affects the small blood vessels in the brain.
It is caused by mutations in the NOTCH3 gene, which leads to the accumulation of a protein called Notch3 in the walls of blood vessels.
This accumulation causes the walls of the blood vessels to become thickened and narrowed, which can lead to strokes.
CADASIL is characterized by recurrent subcortical ischemic strokes, which are strokes that occur in the deep parts of the brain.
Other symptoms of CADASIL include migraines, cognitive impairment, and psychiatric symptoms.
There is currently no cure for CADASIL, and treatment is focused on managing symptoms.
CARASIL
Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) is another hereditary stroke syndrome that affects the small blood vessels in the brain.
It is caused by mutations in the HTRA1 gene, which leads to the accumulation of a protein called HtrA1 in the walls of blood vessels.
Like CADASIL, this accumulation causes the walls of the blood vessels to become thickened and narrowed, which can lead to strokes.
CARASIL is characterized by recurrent subcortical ischemic strokes, as well as other symptoms such as dementia, alopecia, and spine abnormalities.
There is currently no cure for CARASIL, and treatment is focused on managing symptoms.
MELAS
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a hereditary stroke syndrome that affects the mitochondria, which are the energy-producing structures in cells.
It is caused by mutations in the mitochondrial DNA, which can lead to a deficiency in the enzymes that are necessary for energy production.
MELAS is characterized by recurrent stroke-like episodes, which are similar to strokes but are caused by a dysfunction in the mitochondria rather than a blockage in a blood vessel.
Other symptoms of MELAS include seizures, muscle weakness, and headaches. Like others, there is currently no cure for MELAS, and treatment is focused on managing symptoms.
So, hereditary stroke syndromes can result in strokes occurring at a younger age and with greater frequency than in the general population. CADASIL, CARASIL, and MELAS are three examples of hereditary stroke syndromes, each with its own unique set of symptoms and genetic causes.
Other Factors Affecting Risk of Strokes
Lifestyle
Lifestyle factors such as smoking, physical inactivity, and poor diet have been shown to increase the risk of stroke.
These factors can interact with genetic variants to increase the risk of stroke.
For example, a study found that individuals with a genetic variant associated with increased blood pressure had a higher risk of stroke if they also smoked cigarettes.
Another study found that a genetic variant associated with increased cholesterol levels was more strongly associated with stroke in individuals who had a poor diet.
Medical Conditions
Medical conditions such as hypertension, diabetes, and atrial fibrillation also interact with genetic variants to increase the risk of stroke.
For example, a study found that individuals with a genetic variant associated with increased blood pressure had a higher risk of stroke if they also had hypertension.
Another study found that a genetic variant associated with an increased risk of atrial fibrillation was more strongly associated with stroke in individuals who also had diabetes.
Overall, gene-environment interactions play an important role in determining the risk of stroke. Understanding these interactions can help identify individuals at increased risk of stroke and inform prevention strategies.
Final Words
It is important to note that genetic factors do not act alone in determining stroke risk.
Gene-environment interactions also play a critical role in stroke development.
Common genetic variants, variations in specific genes, and gene-environment interactions all contribute to stroke risk. Identifying these genetic risk factors can help in the development of personalized prevention and treatment strategies for stroke.
References:
- https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.116.308398
- https://www.futuremedicine.com/doi/abs/10.2217/pgs.12.14
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200595/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200595/
- Effect of gene–gene and gene – environment interaction on the risk of first‐ever stroke and poststroke death
- Gene–Gene and Gene – Environment Interactions of Polymorphic Loci of Matrix Metalloproteinases in Forming the Risk of Ischemic Stroke
Dr. Heena Arora, a passionate geneticist and microbiologist, is a valuable asset to the Genes Wellness team. Her seminal work includes identifying a key gene for white rust resistance in mustard. Leveraging her deep expertise in genetics and microbiology, she ensures the accuracy and integrity of our content. Dr. Heena’s commitment to knowledge dissemination makes her an integral part of our team.
