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Mutation linked to 42% rise in stroke risk

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A “single genetic mutation can double your risk of stroke”, the Daily Mail has reported.

The newspaper added that scientists hope the discovery could lead to tailored treatments for the condition.

The news is based on research which looked for genetic variations that were more common in people who had had an ischaemic stroke than in people who had not had one. Ischaemic strokes occur when the blood flow to a part of the brain is blocked. They account for 80% of stroke cases. By testing the DNA of several thousand participants, the researchers identified a new genetic variant that was associated with increased risk of a type of ischaemic stroke called a “large vessel stroke”. In large vessel strokes, one or more of the arteries supplying blood to the brain become blocked. People can carry up to two copies of the variant, and the study’s authors estimated that each copy of the variant a person carried was associated with about a 42% increase in the odds of a large vessel stroke. However, it is not yet known whether this genetic variant raises the risk of a stroke, or if it is found near to another variant that is responsible for the increased risk.

This well-designed study has identified a new association between a genetic variation and strokes. However, the study cannot confirm whether the variation itself causes the increased risk of a stroke. This key issue will need to be clarified before these findings can contribute to the development of the new treatments that many newspapers optimistically predicted.

Where did the story come from?

The study was carried out by researchers from the University of Oxford, St George’s, University of London, and a number of other UK and international universities and research institutes. It was funded by The Wellcome Trust. The study was published in the peer-reviewed scientific journal Nature Genetics.

This study was covered by a number of newspapers. In general, the coverage of the research was good, although many news stories focused on its potential to lead to the development of screening tests and new treatments. However, there is no guarantee that this research will lead to such advances. If it does, they are likely to be some way off.

What kind of research was this?

This case-control study aimed to identify genetic factors that are associated with an increased risk of ischaemic strokes. Ischaemic strokes occur when there is a blockage of blood flow to part of the brain. This can deprive brain cells of vital oxygen and nutrients. Around 80% of strokes are ischaemic. The remainder are haemorrhagic strokes, caused by a blood vessel rupturing in or around the brain.

To find genetic variants associated with strokes, the researchers read the DNA sequences of a group of patients who had had an ischaemic stroke. They compared them to the sequences of a group of healthy people. Their theory was that genetic variations that were more common among the stroke group could potentially be linked to stroke risk. To verify whether the variants they initially identified in these groups were associated with strokes, the researchers tested if the same pattern was seen when another group of stroke patients were compared with another group of healthy individuals (controls). This is an accepted method that is used when performing genetic studies of this type.

Although this was a well-designed study, genetic studies like this one can only show that a particular genetic variant is associated with a disease. Further experiments are required to see if the variants identified have a role in causing strokes, or if they lie close to other genetic variants that have this effect. What these variants do still needs to be identified, so media claims that this research could lead to potential new treatments seem premature.

It is also important to remember that genetic, medical and lifestyle factors are likely to contribute to a person’s risk of a stroke. It should not be assumed that a person’s genetics mean that they will definitely have a stroke. Equally, people without high-risk genetics may still be at risk of a stroke risk because of lifestyle factors, such as smoking.

What did the research involve?

In the first phase of the study, researchers recruited 3,548 individuals who had had an ischaemic stroke (the cases) and 5,972 healthy individuals (the controls). The researchers looked for genetic variants that were more common in the stroke group. In a second phase, the researchers confirmed their findings in a new group of 5,859 cases and 6,281 controls.  The new genetic variation they identified was then re-confirmed in a further 735 cases and 28,583 controls.

What were the basic results?

The researchers identified genetic variants at three locations that have been associated with different subtypes of ischaemic stroke in previous studies (near the genes PITX2 and ZFHX3, and on the short arm of chromosome 9). In addition, they identified a genetic variant at a new position within the HDAC9 gene, which was associated with a subtype of ischaemic stroke called large vessel stroke. In large vessel strokes, one or more of the large arteries supplying blood to the brain become blocked. This variant in HDAC9 occurs on about 10% of chromosomes in people in the UK. Humans have two copies of each chromosome, and therefore we can carry up to two copies of this variant (one on each chromosome). The researchers calculated that each copy of the variant that a person possessed was associated with a 42% increase in the odds of having a large vessel stroke (odds ratio 1.42, 95% confidence interval 1.28 to 1.57 for each copy).

How did the researchers interpret the results?

The researchers concluded that they have “identified a new association with the HDAC9 gene region in large vessel stroke”. They also stated that “the mechanism by which variants in the HDAC9 region increase large vessel stroke risk is not immediately clear.”


In this study, researchers have identified a genetic variant in the HDAC9 gene that is associated with a subtype of ischaemic stroke called a large vessel stroke. Large vessel strokes occur when one or more of the arteries supplying blood to the brain become blocked.

In this type of study, the genetic variants identified as being associated with a condition are not necessarily the cause of the increase in risk. Instead, they may lie near another variant that is responsible for the effect. In order to unlock the role of the HDAC9 gene, researchers will now need to study it and the region surrounding it more closely, both to confirm whether the variation in this gene is responsible for the increase in stroke risk and, if so, how it has this effect.

Genetic, medical and lifestyle factors are likely to contribute to stroke risk. In addition, multiple genetic factors may potentially contribute to the risk. It’s important to note that although having higher-risk genetic variants increases the risk of having a stroke, it does not guarantee that a person will have one. Equally, people who do not have any associated variants can still be at risk of a stroke because of lifestyles factors such as smoking, drinking and their diet.

This well-designed study found an association between a new genetic variant and one type of stroke. As yet, it is not possible to say whether this finding will lead to the development of new treatments for large vessel strokes.

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