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NEWS FROM THE AAN ANNUAL MEETING: Genetic Variants in Ischemic Stroke, ICH Risk

Samson, Kurt

doi: 10.1097/01.NT.0000430533.73730.73

Researchers with the International Stroke Genetics Consortium have discovered an association between stroke risk and genetic variations within the oxidative phosphorylation apparatus that provides energy to cells.

Although the underlying pathobiology is not understood, the multi-institutional study found that variants in both nuclear and mitochondrial genes regulating the oxidative phosphorylation (OXPHOS) apparatus increased ischemic stroke and intracerebral hemorrhage (ICH) risk, especially small vessel subtypes.

It is not yet known whether the OXPHOS pathway in such strokes is mediated at the brain tissue level, or influenced by systemic vascular or metabolic risk factors affecting small vessels.The researchers used genetic score analysis — an aggregate measure of risk contributed by all selected variants — to explore possible risk associations, but, while this technique can be effective in aggregating signals, it cannot identify individual causative variants and the team was therefore unable to determine the particular genetic loci conferring risk. Moreover, other common or rare genetic variants may influence the degree to which OXPHOS dysfunction leads to small vessel strokes.

The results were published on Mar. 14 in the journal Stroke, and presented Mar. 20 at the AAN annual meeting in San Diego.

“In an earlier study we found common variants in the mitochondrial genome to be associated with ischemic stroke, and this correlated with white matter hyperintensity volumes in stroke cases,” said researcher Christopher Anderson, MD, an instructor of neurology at Harvard Medical School, and an assistant in neurology at Massachusetts General Hospital. “We wondered if mitochondrial variants were just the tip of the iceberg. Because most OXPHOS genes are in nuclear DNA, we looked at both the mitochodrial and nuclear genomes.”

The team used a permutation-based algorithmic tool to calculate a genetic risk score from OXPHOS genes in the Massachusetts General Hospital's ischemic stroke genome-wide association study (GWAS), and replicated the risk score association in separate data sets comprising individuals from the Ischemic Stroke Genetics Study and Siblings with Ischemic Stroke Study. The risk score was then tested in ICH using individuals from the International Stroke Genetics Consortium ICH-GWAS. A total of 1,643 subjects were in the discovery cohort, with 1,476 and 2,432 individuals in the ICH and ischemic stroke replication cohorts, respectively.

“What we found was an increased risk of ischemic stroke and ICH in individuals with these OXPHOS variants,” Dr. Anderson told Neurology Today in a telephone interview.

The study did not find any associations with large artery or cardioembolic stroke subtypes in ischemic stroke, or the lobar subtype in ICH, but it is possible that sample size in subtype analyses led to false-negatives, he noted.

Both small vessel stroke and deep ICH result from disease of cerebral small vessels and share common risk factors, such as diabetes mellitus and hypertension, but the team could not definitively show that the effect of OXPHOS variants on ischemic stroke or ICH is restricted to small vessel ischemic or deep ICH subtypes.

“Our findings suggest a possible shared genetic contribution to small vessel pathobiology underlying small vessel stroke and deep ICH, which could be mediated through disruption in oxidative function at the tissue level or through modification of upstream systemic or endothelial risk factors shared by the two types of stroke,” Dr. Anderson said.

However, because OXPHOS dysfunction can result in numerous physiological problems, including ATP depletion, antioxidant generation, cell signaling defects, and alteration in apoptotic thresholds, the reported associations “cannot directly inform the underlying pathobiology of this small vessel link,” according to the investigators. To build upon the research, functional studies of the mechanisms of energy conversion dysfunction will be necessary, they said.

The OXPHOS apparatus consists of five protein complexes that reside in the inner membrane of the mitochondria; named Complex 1 through 5, they are necessary for cellular aerobic respiration and generation of ATP.

Rare mutations in these complexes can also lead to severe OXPHOS dysfunction in a number of inherited mitochondrial syndromes with multiple phenotypes, including stroke. These can cause a full range of conditions throughout the body, as well as myopathy in the body and encephalopathy in the brain.

These five complexes “function as a coordinated system rather than a straight line,” Dr. Anderson explained, adding that in children with mitochondrial disease, many have defects in complexes 1 and 4. “These are like the bottlenecks of the system. Complex 1 carries a large burden of risk. Those with severe defects in complex 5 do not make it to birth.”

The researchers found that OXPHOS variants overall increased ischemic stroke risk by 17 percent, with variants in Complex 1 increasing risk by 6 percent. Complex 1 variants increased risk of small vessel ischemic stroke by 15 percent, while variants in Complex 4 raised this risk by 14 percent. Complex 4 variants were also associated with an 8 percent increase in risk of deep hemipheric stroke.

“The more variants, the higher the risk, it appears; but we do not know how they are doing it and cannot create genetic tests that will explain this risk. It appears that small defects in these complexes may exert tiny effects over a lifetime that culminate in ICH and ischemic stroke, similar to having high blood pressure.”

“This study is very important because it is part of an emerging body of research pointing to different genetic variables in disease states for which a single genetic approach will not be enough,” said neurologist John M. Shoffner, MD, president of the Foundation for Mitochondrial Medicine and director of the molecular laboratory at Medical Neurogenetics, LLC, in Atlanta, GA.

Dr. Shoffner, who has studied mitochondrial dysfunction in neurological disease for more than 25 years, and authored over 70 research publications, said that a variety of factors might explain why small vessels are especially vulnerable to variants in the OXPHOS complex and why some people are more vulnerable than others.

“Perhaps it is due to functional reserve.The cellular energy process is like plumbing in a house, with an inflow of substrates and outflow of ATP. If part of the system is broken, there will be problems,” he explained. “But the extent of the problem varies as well as the specific mechanisms that are affected, and it appears that these variants by some shared genetic effect(s) influence this — something that is nicely presented in this paper.”

However, the findings also emphasize some standard correlation between mitochondrial variants, small vessel pathobiology, and these strokes.

“From what we understand about mitochondrial disease and stroke, we can see that small vessels are significantly involved in many ways including metabolic function and mechanisms controlling vasoconstriction/vasodilatation,” Dr. Shoffner said. “It is important to remember that these effects are not restricted to just the small vessels and their vascular distribution, but also to the neurological tissue served by these vessels, so it appears to be a combined effect.”

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•. Anderson CD, Biffi A, Nalls MA, et al.on behalf of the International Stroke Genetics Consortium. Common variants within oxidative phosphorylation genes influence stroke and intracerebral hemorrhage. Stroke 2013;44:612–619.
    •. Anderson CD, Biffi A, Rahman R, et al.on behalf of the International Stroke Genetics Consortium. Common mitochondrial sequence variants in ischemic stroke. Ann Neurol 2011;69:471–480.
      •. Rost NS, Anderson CD, Biffi A, et al.White matter hyperintensity burden and susceptibility to cerebral ischemia. Stroke 2010;41:2807–2811.
        •. Neurology Today feature about Dr. Christopher Anderson, an AAN Brain Foundation Fellow:
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