Genetic risk factors for spontaneous intracerebral haemorrhage

Carpenter, Amanda; Singh, Inder Paul; Gandhi, Chirag D.; Prestigiacomo, Charles J.

doi:10.1038/nrneurol.2015.226

Cited by 76 publications

(56 citation statements)

References 120 publications

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“…25 Promising candidates for risk alleles in ICH identified in populations (which had no continental Africans), include variants of the genes Apolipoprotein E ( APOE ), ACE, PMF1/SLC25A44 , COL4A2 , and MTHFR 18, 23, 26 . Other genetic variants related to hemostasis, lipid metabolism, inflammation, and the central nervous system microenvironment as well as the locus 1q22 25 have also been linked to ICH in single candidate gene studies.…”

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confidence: 99%

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Advancing stroke genomic research in the age of Trans-Omics big data science: Emerging priorities and opportunities

Owolabi

Peprah

et al. 2017

Journal of the Neurological Sciences

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Background We systematically reviewed the genetic variants associated with stroke in genome-wide association studies (GWAS) and examined the emerging priorities and opportunities for rapidly advancing stroke research in the era of Trans-Omics science. Methods Using the PRISMA guideline, we searched PubMed and NHGRI- EBI GWAS catalog for stroke studies from 2007 till May 2017. Results We included 31 studies. The major challenge is that the few validated variants could not account for the full genetic risk of stroke and have not been translated for clinical use. None of the studies included continental Africans. Genomic study of stroke among Africans presents a unique opportunity for the discovery, validation, functional annotation, trans-omics study and translation of genomic determinants of stroke with implications for global populations. This is because all humans originated from Africa, a continent with a unique genomic architecture and a distinctive epidemiology of stroke; as well as substantially higher heritability and resolution of fine mapping of stroke genes. Conclusion Understanding the genomic determinants of stroke and the corresponding molecular mechanisms will revolutionize the development of a new set of precise biomarkers for stroke prediction, diagnosis and prognostic estimates as well as personalized interventions for reducing the global burden of stroke.

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confidence: 99%

“…Other genetic variants related to hemostasis, lipid metabolism, inflammation, and the central nervous system microenvironment as well as the locus 1q22 25 have also been linked to ICH in single candidate gene studies. 26 …”

Section: 0 Discussionmentioning

confidence: 99%

Advancing stroke genomic research in the age of Trans-Omics big data science: Emerging priorities and opportunities

Owolabi

Peprah

et al. 2017

Journal of the Neurological Sciences

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“…Although life-style factors such as tobacco/alcohol consumption, hypertension, trauma, anti-coagulant, and anti-platelet therapies have been implicated in ICH pathobiology, relatively little is known about the extent to which familial and hereditary factors contribute to spontaneous ICH in humans. In a recent review of the known human genetic risk factors for ICH, Carpenter et al, have shown, based on previous meta analyses and genet-association studies, several genes to be implicated in ICH pathobiology (Carpenter et al, 2015). They suggest that mutations in genes regulating the processes of hemostasis, lipid metabolism and transfer, as well as inflammation (APOE, ACE, PMF1/SLC25A44, COL4A2, and MTHFR) can predispose individuals to spontaneous ICH (Carpenter et al, 2015).…”

Section: Conclusion/discussionmentioning

confidence: 99%

“…In a recent review of the known human genetic risk factors for ICH, Carpenter et al, have shown, based on previous meta analyses and genet-association studies, several genes to be implicated in ICH pathobiology (Carpenter et al, 2015). They suggest that mutations in genes regulating the processes of hemostasis, lipid metabolism and transfer, as well as inflammation (APOE, ACE, PMF1/SLC25A44, COL4A2, and MTHFR) can predispose individuals to spontaneous ICH (Carpenter et al, 2015). Although such gene-association studies do not yield mechanistic insights into how deficiencies in these gene products may contribute to the etiology of spontaneous ICH, they do offer candidate pathways as points of therapeutic intervention to prevent vascular leakage.…”

Section: Conclusion/discussionmentioning

confidence: 99%

Etiology of intracerebral hemorrhage (ICH): novel insights from Zebrafish embryos

Eisa-Beygi

Rezaei²

2016

Int. J. Dev. Biol.

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Intracerebral hemorrhage (ICH) is the most severe subtype of stroke. Treatment options are scarce and given the high morbidity and mortality, relatively ineffective. Since patients with ICH may have an unknown heritable component, the need to identify potential risk factors necessitates the use of animal models to elucidate the genetic underpinnings of neurovascular development and, thereby, identify candidate regulatory pathways that are likely to be disrupted in patients with ICH. Zebrafish (Danio rerio) exhibits the anatomical and physiological complexity of a closed circulatory system observed in all vertebrates (with arteries, veins and capillaries). Moreover, studies over the last decade, aided by the application of chemical mutagenesis screens, morpholino mediated knockdown approaches and tissue-specific transgenic markers, have paved the way for the identification of several genes and signaling pathways that regulate developmental neurovascular stabilization. We hypothesize that mutations in these genes or pharmacological perturbations of these gene-products may account, at least in part, for the etiology of some forms of spontaneous ICH in humans.

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“…Instead of looking at these patients as individuals with SCD who typically happen to be black, we believe a better approach is to view them as individuals with predominantly African genetic heritage who also happen to have SCD, which can be seen as a significant stressor in the presence of which otherwise minor variants with little health impact in isolation become important determinants of health. We discuss exemplary domains in which genomic studies have yielded promising results in populations without SCD including (1) APOE, specifically the prevalence of the APOE‐ε4 ; (2) genes identified from African or African American studies predisposing to hypertension; (3) APOL1 G1/G2 variants; (4) haptoglobin haplotype (H2/2 allelic pattern); and (5) other genes associated with intracerebral hemorrhage including ACE, PMF1/SLC25A44, COL4A2, and MTHFR …”

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confidence: 99%

New approaches to genetic predisposition for hemorrhagic stroke in sickle cell disease

Adams

Akinyemi

Owolabi

et al. 2018

J of Clinical Hypertension

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Hypertension has not traditionally been considered a significant problem in sickle cell disease (SCD) but that view is changing. 1 In the general population hypertension leads, among other things, to small vessel disease of the kidney and brain and to intracerebral hemorrhage, which are important complications of SCD. Although SCD is the most common monogenetic disease, its wide phenotypic variation has, for the most part, eluded satisfactory explanation. Except for coinheritance of alpha thalassemia and certain genes that affect fetal hemoglobin production, genomic studies have not converged on clear genetic risk markers for important complications such as stroke 2 although promising candidates have recently been proposed. 3 Specific genomic risk indicators for intracranial hemorrhage have not been reported. Although first ischemic stroke has been greatly reduced by regular red cell transfusion initiated on the basis of risk stratification by transcranial Doppler ultrasound 4 (STOP Protocol) there has been no corresponding reduction in intracranial hemorrhage inSCD. 5 With increased survival and decreased burden of ischemic stroke, intracerebral hemorrhage (ICH) will become an increasingly important problem. Robust predictors could lead to targeted prevention and reduction of this important type of stroke.Our understanding of risk for hemorrhagic stroke in SCD comes primarily from the Cooperative Study of Sickle Cell Disease. 6 This was an important effort to characterize the common phenotypes including stroke (ischemic and hemorrhage) but these data are over 30 years and the hemorrhagic stroke predictive model was based on only 27 events.Transcranial Doppler ultrasound is very effective in guiding transfusion or hydroxyurea to prevent ischemic stroke but does not clearly identify those at risk for hemorrhagic stroke. The existing phenotype-based risk model from the cooperative study is not specific enough to support clinical trials. There is a critical need to modernize our research strategies to find robust models if we are to reduce hemorrhagic stroke.We propose a shift in perspective. For example, in patients without SCD, several genes have been linked to intracerebral hemorrhage. 7 Ongoing efforts are developing stroke genomics from an African perspective 8,9 including achieving a better understanding of the genomics of predisposing factors such as hypertension. 10 The H3Africa Project was established by the US National Institutes of Health and the Wellcome Trust to develop capacity in genomic research in Africa, including specific projects focusing on assessment of perceptions about public health interventions to increase awareness, early detection and prevention of SCD-related complications 11 and the Sickle Pan-African Research Consortium (SPARCO) 12 that aims to develop infrastructure for sickle cell disease research, health care, education, and training in Africa. Instead of looking at thesepatients as individuals with SCD who typically happen to be black, we believe a better approach is to view them a...

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Genetic risk factors for spontaneous intracerebral haemorrhage

Cited by 76 publications

References 120 publications

Advancing stroke genomic research in the age of Trans-Omics big data science: Emerging priorities and opportunities

Advancing stroke genomic research in the age of Trans-Omics big data science: Emerging priorities and opportunities

Etiology of intracerebral hemorrhage (ICH): novel insights from Zebrafish embryos

New approaches to genetic predisposition for hemorrhagic stroke in sickle cell disease

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