Genes as early warning systems

Strokes are the second most common cause of death worldwide, and the leading cause of physical disabilities in adults. Approximately 80% of all cases of stroke are the result of ischemia, i.e. an acute lack of oxygen owing to the obstruction of blood flow through a cerebral artery in the brain. The individual level of risk for ischemic stroke is determined by a combination of genetic factors and pre-existing disorders, such as high blood pressure and diabetes. In collaboration with researchers at Cambridge University and the Baker Heart and Diabetes Institute in Melbourne, Professor Martin Dichgans (LMU Medical Center) has now shown that genetic data obtained from a single sample of blood or saliva can identify persons who have a three-fold higher risk (than the average for the population as a whole) of suffering an ischemic stroke. Moreover, this genetically based estimate of risk is as reliable, or even more so, than that based on the assessment of conventionally recognized clinical risk factors. Based on these results, the authors of the study conclude that individuals with a high genetic risk may need more meticulous monitoring and more intensive preventive interventions than current guidelines suggest. The new findings appear today in the online journal Nature Communications.The collaboration first used a machine learning approach to analyze a large body of genetic data obtained by a variety of research groups in genome-wide association studies that identified gene variants which can be correlated with increased risk of stroke. On the basis of this analysis, they assigned an individual genetic risk score to each combination of pre-disposing variants. They then tested the predictive value of these risk scores by comparing them with data from a long-term prospective study, which has collected health-related information, including genomic data, from 420,000 individuals. These data are now archived in the UK Biobank. The results of their comparative analysis demonstrated that the new genetic estimator of stroke risk is more precise than those employed up to now, and is comparable in reliability to other estimates based on known behavioral or physiological factors such as cigarette smoking or body mass index (BMI). Moreover, the genetic risk score is a significantly more successful predictor of future episodes of ischemic stroke than an evaluation of the medical histories of a subject’s family. – Indeed, the new risk score is accurate enough to predict whether or not any given individual belongs to the 0.25% of patients who have a three-fold higher risk of stroke than the population average.The genomic risk assessment is derived from the genomic DNA, the sequence of which is unique to each individual, and has significant advantages over evaluations based on established risk factors, because it can be used from birth to estimate the risk of stroke. This makes it possible to initiate preventive strategies before patients develop any of the conditions that now serve as conventional risk factors for stroke, such as high blood pressure or high levels of fats in the bloodstream, said Martin Dichgans, Professor of Neurology and Director of the Institute for Stroke and Dementia Research (ISD) at the LMU Medical Center, and one of the co-leaders of the new study.The authors underline the fact that people with a high genetic risk for ischemic stroke can still reduce this risk by minimizing their exposure to conventional risk factors – for example, by taking steps to reduce blood pressure and BMI and giving up smoking.“The sequencing of the human genome has revealed many insights. For common diseases, such as stroke, it is clear that genetics is not destiny; however, each person does have their own innate risk for any particular disease. The challenge is now how we best incorporate this risk information into clinical practice so that the public can live healthier and longer,” says Dr. Michael Inouye of the Baker Heart and Diabetes Institute and the University of Cambridge, another leader of the study.The new genomic risk assessment is also detects significant differences in risk levels between individuals whom currently recommended guidelines assign to the same risk category. The researchers therefore suggest that the clinical guidelines now in place may be inadequate for persons with a high genomic risk score for stroke, since such individuals might well need more intensive interventions to counteract the increased risk. The new method of risk assessment can help to pinpoint the modifiable risk factors that need to be mitigated in order to reduce this risk to an acceptable level, as well as enabling more effective early interventions for persons at high risk of stroke and other cardiovascular diseases.Nature Communications 2019