The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer reviewed.
Key Takeaway
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When added to clinical risk factors, a validated genomic risk score can predict the lifetime risk of intracerebral hemorrhage in individuals of European ancestry.
Why This Matters
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Prediction for intracerebral hemorrhage could be improved by adding genomic information to known clinical risk factors, thereby improving decision-making in clinical practice, and potentially improving outcomes with preventive measures.
Study Design
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The study used a meta-analytic approach to formulate individual genomic risk scores for 21 intracerebral hemorrhage-related traits, using data from three genomewide association studies: the North America multicenter Genetics of Cerebral Hemorrhage on Anticoagulation (GOCHA) study, the International Stroke Genetics Consortium (EUR/ISGC), and the Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study.
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The GOCHA and EUR/ISGC datasets were used as the training datasets and the GERFHS was used as the primary validation dataset.
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The UK Biobank (general population sample) was also used for external validation.
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All the patients were from European-only populations.
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The patients with intracerebral hemorrhage had new acute neurological deficits, confirmed by computed tomography or magnetic resonance imaging. They did not have evidence of other underlying causes of intracerebral hemorrhage.
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The patients in the control group were from the same population but did not have intracerebral hemorrhages.
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The investigators evaluated the associations of the metagenomic risk score with intracerebral hemorrhage and how well the metagenomic risk score worked to predict intracerebral hemorrhage.
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They also assessed the associations with the risk of incident intracerebral hemorrhage in the UK Biobank cohort (general population).
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The association of the metagenomic risk score with intracerebral hemorrhage was measured using logistic regression.
Key Results
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The adjusted results (for age, sex, and two principal components) showed that a 1 standard deviation increase in the metagenomic risk score was associated with a 45% greater chance of having intracerebral hemorrhage (odds ratio [OR], 1.45; 95% CI, 1.30 – 1.63; P = 6.2 x 10–11).
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There was a progressively higher risk for intracerebral hemorrhage in the higher levels of the metagenomic risk scores. The patients in the top 1% (P = .01) and 2.5% (P = 5.77 x 10–4) were significantly more likely to have intracerebral hemorrhage than the rest of the individuals.
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The clinical risk factors most strongly associated with risk of intracerebral hemorrhage were history of ischemic stroke, hypertension, diabetes, hypercholesterolemia, heavy alcohol use, anticoagulant use, and education less than high school. When these factors were adjusted for, the metagenomic risk scores were still independently associated with the risk of intracerebral hemorrhage (P < .0001). When the metagenomic risk scores were combined with the clinical risk factors, the association was even higher.
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When looking at different location-specific subtypes of intracerebral hemorrhage, there was a greater chance of both lobar (P = 5 x 10–4) and nonlobar (P = 2.4 x 10–5) intracerebral hemorrhage for every 1 standard deviation of the metagenomic risk score after adjustment for clinical risk factors.
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When looking at the general population sample, the metagenomic risk scores were also associated with a higher risk of incident intracerebral hemorrhage (P = 7 x 10–7).
Limitations
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The sample sizes for the datasets for intracerebral hemorrhage are smaller than for other clinical entities, which can affect the estimates of association between the genetic variants and the risk of intracerebral hemorrhage.
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Since intracerebral hemorrhage can present differently and in different locations, the investigators pooled cases; this may have affected the predictive performance for the specific etiologies of intracerebral hemorrhage.
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Even though the metagenomic risk score demonstrated significant associations with the risk of incident intracerebral hemorrhage in the general population cohort, the investigators could not look at its effects with other clinical predictors because the metagenomic risk score was made using associations with these predictors in datasets including data from the general population cohort.
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The outcomes may not be generalizable to populations with other ancestries, as this study only used data from individuals of European ancestry.
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Procedures for genomic risk scores are not standardized, which can affect consistency and reproducibility.
Disclosures
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Hyacinth I. Hyacinth has consulted for Acuta Capital, Novartis, and Nutriglobal and is supported by the National Institutes of Health (NIH).
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Jonathan Rosand has consulted for Takeda Pharmaceuticals.
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Christopher D. Anderson has consulted for ApoPharma and Invitae and also received Sponsored Research Support from Bayer AG, the American Heart Association (AHA), and Massachusetts General Hospital.
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Marios K. Georgakis is supported by a Walter-Benjamin fellowship from the German Research Foundation and the FöFoLe program of LMU Munich.
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Guido J. Falcone is supported by the NIH, the AHA, and a pilot grant from the Claude D. Pepper Older Americans Independence Center at Yale.
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Jonathan Rosand and Christopher D. Anderson are supported by the NIH, AHA, and AHA-Bugher.
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Other funding was received from NIH-National Institute of Neurologic Disorders and Stroke, the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke, the Keane Stroke Genetics Research Fund, the Edward and Maybeth Sonn Research Fund, the University of Michigan General Clinical Research Center, the National Center for Research Resources, a Greater Cincinnati Foundation Grant, Ministerio de Sanidad y Consumo de España, Instituto de Salud Carlos III, Contract for Research Training for Professionals with Specialty, “Ramon y Cajal” Postdoctoral Contract, Spanish Research Networks “Red HERACLES,” Spanish government grants, Polish Ministry of Education grant, the Lund University, Region Skåne and the Swedish Medical Research Council, the Swedish Stroke Association, the Freemasons Lodge of Instruction EOS in Lund, and the King Gustaf V and Queen Victoria’s foundations.
This is a summary of a preprint research study, “A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage,” written by Evangelos Pavlos Myserlis, MD, from the Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, and colleagues, on MedRxiv provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.
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