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  • 1
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    Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Neurology Vol. 92, No. 5 ( 2019-01-29)
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 92, No. 5 ( 2019-01-29)
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000006851
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1491874-2
    detail.hit.zdb_id: 207147-2
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  • 2
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    Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke
    Oxford University Press (OUP) ; 2017
    In:  Brain Vol. 140, No. 10 ( 2017-10-01), p. 2663-2672
    Details
    In: Brain, Oxford University Press (OUP), Vol. 140, No. 10 ( 2017-10-01), p. 2663-2672
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awx220
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 1474117-9
    detail.hit.zdb_id: 80072-7
    SSG: 12
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  • 3
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    Abstract MP40: Klotho -vS Heterozygosity is Associated With Lower Risk of Lobar Intracerebral Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Stroke Vol. 52, No. Suppl_1 ( 2021-03)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. Suppl_1 ( 2021-03)
    Abstract: Introduction: Klotho is a transmembrane protein highly expressed in the kidneys and choroid plexus. Klotho modulates insulin sensitivity and suppresses oxidative stress. Two missense variants in the Klotho gene ( KL ) form the functional haplotype KL-VS . Heterozygosity for KL-VS ( KL-VS-Het+ ) increases serum levels of Klotho and attenuates the excess risk of Alzheimer’s Disease conferred by APOE epsilon 4. We tested the hypothesis that KL-VS-Het+ lowers the risk of spontaneous intracerebral hemorrhage (ICH) and the excess in this risk conferred by the APOE epsilon variants. Methods: We conducted a genetic association study that combined publicly available data from 3 case-control studies of ICH in Europeans. We identified the two genetic variants that define KL-VS (rs9536314 and rs9527025) and the two genetic variants that define the APOE epsilon alleles (rs429358 and rs7412). We tested for association between KL-VS-Het+ and ICH risk via study-specific logistic regression followed by fixed-effects, inverse-variance weighted meta-analysis using I 2 to quantify heterogeneity. Given the known biological differences between lobar and non-lobar ICH, we conducted stratified analyses based on location. Additionally, we evaluated the role of KL-VS-Het+ in carriers of APOE epsilon 2 and 4 variants. Results: A total of 1066 ICH cases (464 lobar and 602 non-lobar) and 1073 controls were included in the study (mean age 69 [SD 14], female sex 919 [47%] ). KL-VS-Het+, present in 554 (26%) participants, was associated with a lower risk of ICH (OR 0.81, 95%CI 0.67-0.99; p=0.04) without heterogeneity across studies (I 2 =0%). Stratified analyses indicated that KL-VS-Het+ was associated with a lower risk of lobar ICH (OR 0.68, 95%CI 0.52-0.88; p=0.004) but not of non-lobar ICH (OR 0.92, 95%CI 0.73-1.16; p=0.48). In secondary analyses, KL-VS-Het+ was associated with a lower risk of ICH in carriers of APOE epsilon 2 (OR 0.52, 95%CI 0.28-0.96; p=0.037; I 2 =0%) but not epsilon 4 (OR 0.82, 95%CI 0.5-1.33; p=0.42). Conclusion: KL-VS -Het+ is associated with a lower risk of ICH. This protective association was stronger in lobar hemorrhages and in carriers of APOE epsilon 2. Further research should evaluate these associations in non-Europeans and identify the mediating molecular pathways.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.52.suppl_1.MP40
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 80381-9
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  • 4
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    Abstract T P153: APOE e4 Increases Risk of Recurrent Non-lobar Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. suppl_1 ( 2015-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. suppl_1 ( 2015-02)
    Abstract: Introduction: Genetic variants ε2 / ε4 within the APOE gene are established risk factors for lobar intracerebral Hemorrhage (ICH) and its recurrence. Data from a large case-control meta-analysis suggest a potential but not yet replicated role for APOE ε4 in risk of non-lobar ICH. Hypothesis: APOE ε4 increases risk of recurrent non-lobar ICH and, replicating prior results, increases risk of initial non-lobar ICH. Methods: Among consecutive non-lobar ICH cases from our single center series (n=468), 363 survivors were followed for recurrence. All subjects had clinical and demographic data, and APOE genotype determined at the time of index ICH. In a separate case-control analysis, 156 non-lobar ICH cases and 152 ICH-free controls, ascertained subsequent to all prior publications, were analyzed as replication of previously published case-control findings. These case-control results were then meta-analyzed with previously published data. Results: We observed 29 non-lobar-ICH recurrences among 363 survivors. APOE ε4 was associated with non-lobar-ICH recurrence (HR = 1.31, 95% CI =1.02 - 2.69, p = 0.038) after adjustment for age / gender / ethnicity and cardiovascular risk factors. Case-control analyses of newly ascertained subjects replicated the APOE ε4 association with risk of non-lobar ICH (OR = 1.31, 95% CI = 1.02-1.68, p = 0.035). Meta-analysis of these with published case-control data returned an association between ε4 and non-lobar ICH (OR = 1.21, 95% CI = 1.11-1.32, p = 1.5 x 10 -5 ). No associations were identified between APOE ε2 and non-lobar ICH risk or recurrence. Conclusions: APOE ε4, but not ε2 is associated with risk and recurrence of non-lobar ICH. Whether APOE’s role in non-lobar ICH involves beta-amyloid pathology, its presumed mechanism in lobar ICH, requires further study.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.46.suppl_1.tp153
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 80381-9
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  • 5
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    Genome-Wide Association Analysis of Ischemic Stroke in Young Adults
    Oxford University Press (OUP) ; 2011
    In:  G3 Genes|Genomes|Genetics Vol. 1, No. 6 ( 2011-11-01), p. 505-514
    Details
    In: G3 Genes|Genomes|Genetics, Oxford University Press (OUP), Vol. 1, No. 6 ( 2011-11-01), p. 505-514
    Abstract: Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15–49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P & lt; 5 × 10−8), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 × 10−7) and rs1986743 (in ARL6IP6; P = 2.7 × 10−7), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults.
    Type of Medium: Online Resource
    ISSN: 2160-1836
    URL: Article
    DOI: 10.1534/g3.111.001164
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2011
    detail.hit.zdb_id: 2629978-1
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  • 6
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    APOE genotype, hypertension severity and outcomes after intracerebral haemorrhage
    Oxford University Press (OUP) ; 2019
    In:  Brain Communications Vol. 1, No. 1 ( 2019-01-01)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 1, No. 1 ( 2019-01-01)
    Abstract: Intracerebral haemorrhage in the elderly is a severe manifestation of common forms of cerebral small vessel disease. Nearly 60% of intracerebral haemorrhage survivors will develop clinical manifestations of small vessel disease progression including recurrent haemorrhage, ischaemic stroke, dementia, late-life depression and gait impairment within 5 years. Blood pressure measurements following intracerebral haemorrhage are strongly associated with this risk. However, aggressive blood pressure lowering in the elderly carries substantial risks. In order to determine whether there might be an opportunity to select individuals at the highest risk for small vessel disease progression for aggressive blood pressure reduction, we investigated whether APOE gene variants ɛ2/ɛ4 modify the association between blood pressure and small vessel disease clinical progression after intracerebral haemorrhage. We conducted a single-centre longitudinal study at a tertiary care referral centre (Massachusetts General Hospital in Boston, MA, USA), analysing 716 consecutive survivors of acute intracerebral haemorrhage, enrolled from January 2006 to December 2016. We conducted research interviews at the time of enrolment and obtained APOE genotypes from peripheral venous blood samples. We followed patients longitudinally by means of validated phone-based research encounters, aimed at gathering measurements of systolic and diastolic blood pressure, as well as information on small vessel disease clinical outcomes (including recurrent haemorrhage, incident ischaemic stroke, incident dementia, incident depression and incident gait impairment). APOE ε4 and systolic blood pressure were associated with the risk of recurrent haemorrhage, ischaemic stroke and post-haemorrhage dementia, depression and gait impairment (all P  & lt; 0.05). APOE ε4 and systolic blood pressure interacted to increase the risk of recurrent haemorrhage, ischaemic stroke, dementia and gait impairment (all interaction P  & lt; 0.05). Among patients with elevated blood pressure following intracerebral haemorrhage (average systolic blood pressure 120–129 mmHg and diastolic blood pressure & lt;80 mmHg) only those with one or more APOE ε4 copies were at increased risk for one or more small vessel disease outcomes (hazard ratio = 1.97, 95% confidence interval 1.17–3.31). Among haemorrhage survivors with hypertension (stage 1 and beyond) APOE genotype also stratified risk for all small vessel disease outcomes. In conclusion, APOE genotype modifies the already strong association of hypertension with multiple small vessel disease clinical outcomes among intracerebral haemorrhage survivors. These data raise the possibility that genetic screening could inform blood pressure treatment goals in this patient population.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcz018
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 3020013-1
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  • 7
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    Abstract W MP90: APOE Variants are Associated With Increased Risk of Warfarin-Related Intracerebral Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. suppl_1 ( 2014-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. suppl_1 ( 2014-02)
    Abstract: Background: Epsilon (e) variants in the Apolipoprotein E (APOE) gene are well-established risk factors for spontaneous intracerebral hemorrhage (s-ICH). We tested the hypothesis that APOE-e variants are also associated with warfarin-related ICH (w-ICH) and examined interactions between APOE and warfarin. Methods: Prospective multicenter 2-stage (discovery and replication) study. ICH was classified as lobar and non-lobar based on admission head CT. In the discovery stage, w-ICH cases were matched with warfarin-exposed controls (w-controls). In replication, w-ICH cases were matched with non-warfarin controls (nw-controls). APOE was directly genotyped. Association testing was performed using multivariable logistic regression. Gene-environment interaction between APOE and warfarin was formally tested using a case only approach (combining s-ICH and w-ICH cases). Results: The discovery stage included 316 w-ICHs (43% lobar and 57% non-lobar) and 355 w-controls. Results are presented in the Table: APOE-e2 was associated with lobar and non-lobar w-ICH, and APOE-e4 was associated with lobar but not with non-lobar w-ICH. In case-only analysis, 885 s-ICHs were combined with w-ICHs (total n=1201) and no evidence of interaction between APOE and warfarin was found (all p 〉 0.20). The replication included 63 w-ICHs (44% lobar and 56% non-lobar) and 990 nw-controls. The distribution of APOE variants was similar in w-controls (discovery) and nw-controls (replication) for both e2 (p=0.81) and e4 (p=0.88). In replication, APOE-e2 and e4 were associated with lobar but not with non-lobar w-ICH. Conclusions: APOE-e variants constitute strong risk factors for lobar w-ICH. An effect may also exist between APOE-e2 and non-lobar hemorrhages, but given the lack of replication larger sample sizes are required to properly assess this association. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.45.suppl_1.wmp90
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 80381-9
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  • 8
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    Abstract 54: APOE Genotype Modifies the Effect of Blood Pressure on Long-term Clinical Deterioration Following Intracerebral Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Stroke Vol. 48, No. suppl_1 ( 2017-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 48, No. suppl_1 ( 2017-02)
    Abstract: Introduction: Intracerebral Hemorrhage (ICH) is a severe manifestation of cerebral small vessel disease, and identifies individuals at high risk for recurrent ICH, ischemic stroke, dementia, late-life depression and gait impairment. Blood pressure (BP) following ICH is strongly associated with risk of these clinical sequelae. Hypothesis: We sought to test whether the most potent genetic risk factors for ICH recurrence, APOE ε2 / ε4, modify the effect of BP. Methods: We prospectively collected demographic and medical data for 608 consecutive ICH survivors, presenting to a single center from January 2006 to December 2013. APOE genotyping was performed on samples obtained via peripheral venous blood draw. Participants were followed longitudinally with periodic BP measurements and evaluation of recurrent ICH / ischemic stroke events. We assessed cognitive and psychiatric outcomes of interest using two validated scales: 1) Telephone Interview for Cognitive Status (TICS); 2) 4-item version of the Geriatric Depression Scale (GDS-4). We generated multivariable Cox models for each outcome, and for overall risk of clinical deterioration (i.e. developing any outcome of interest). Results: APOE ε4 and systolic BP (SBP) interacted to increase risk of ICH recurrence, small vessel ischemic stroke, dementia, and gait impairment after ICH (all p 〈 0.05). Among patients with average SBP 120-129 mmHg only ε4 carriers were at increased risk for clinical deterioration (Hazard Ratio = 1.67, 95% Confidence Interval 1.06-2.64, p = 0.029). ICH survivors with SBP≥130 mmHg were also at increased risk, with APOE genotype further increasing risk among those with one or more ε4 copies (Figure). Conclusions: APOE ε4 modifies the effect of BP on clinical deterioration risk following ICH, and may identify individuals most likely to benefit from aggressive BP reduction. These data raise the possibility of genetic screening informing hypertension treatment goals in ICH survivors.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.48.suppl_1.54
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 80381-9
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  • 9
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    Abstract WP359: Higher Risk of Intracerebral Hemorrhage Recurrence Among African American and Latino/Hispanic Individuals
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Stroke Vol. 48, No. suppl_1 ( 2017-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 48, No. suppl_1 ( 2017-02)
    Abstract: Introduction: Intracerebral hemorrhage (ICH) is more prevalent among African American (AA) and Latino/Hispanic (LH) individuals. While ICH survivors are at high risk for rebleeding, it is unclear whether recurrence risk differs based on race / ethnicity. Hypothesis: We sought to clarify: 1) whether ICH recurrence risk is higher for AA and LH patients; 2) whether this disparity is explained by the most potent ICH risk factors, i.e. hypertension severity and the APOE gene variant ε4. Methods: We conducted a single-center longitudinal study enrolling 738 ICH survivors presenting to a single center from January 2006 to December 2014. Participants had APOE genotype determined at enrollment, and were followed via phone calls and review of medical records. We captured hypertension severity as absolute blood pressure (BP) measures, as well as BP variability (average percent variation during follow-up). We created univariable and multivariable (Cox regression) models to identify risk factors for ICH recurrence. Results: Systolic BP (SBP) was associated with increased ICH recurrence risk ( Hazard Ratio [HR]=1.30, 95% Confidence Interval [CI] 1.02 -1.66, p=0.036), as was SBP variation (HR=1.75 per variation quartile, 95% CI 1.09-2.81, p=0.021). APOE ε4 was also associated with ICH recurrence (HR=1.66, 95% CI 1.10-2.50, p=0.016). After adjusting for BP and APOE ε4, both LH ( HR=1.68, 95% CI 1.01-2.78, p = 0.045 ) and AA ( HR= 2.12, 95% CI 1.14-3.95, p = 0.019 ) patients when at higher risk for ICH recurrence. Both AA and LH patients had a significantly higher systolic BP (SBP) during follow-up (Figure, A); AA individuals also had greater SBP variation during follow up (Figure, B ). Conclusions: AA and LH patients are at higher risk for ICH recurrence, and hypertension severity / APOE ε4 did not fully account for this disparity. Additional studies will be required to further elucidate biological determinants for this health
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.48.suppl_1.wp359
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 10
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    Abstract 15: Medication Inadequacy Accounts for Two-Third of Uncontrolled Hypertension Following Intracerebral Hemorrhage in a Multinational Study
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. Suppl_1 ( 2020-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. Suppl_1 ( 2020-02)
    Abstract: Introduction: Intracerebral hemorrhage (ICH) survivors often have severe hypertension and require multiple antihypertensive agents for blood pressure (BP) control. Adequate BP control is vital for ICH prevention, but the majority of ICH survivors have uncontrolled hypertension. To understand how we might improve BP control, we aimed to identify contributors to uncontrolled hypertension, and determine antihypertensive requirements as well as predictors of the need of ≥3 antihypertensives after ICH. Methods: We studied 1172 ICH survivors from two independent ICH cohorts: Massachusetts General Hospital (MGH) and the University of Hong Kong (HKU). We defined uncontrolled hypertension (BP ≥140/90 mmHg), inadequately medicated hypertension (uncontrolled hypertension on ≤2 antihypertensives), and resistant hypertension (uncontrolled hypertension on ≥3 antihypertensive classes or controlled hypertension on ≥4 classes) six months after ICH. Baseline predictors of the need for ≥3 antihypertensive agents were derived using multivariate logistic regression. Results: At six months post-ICH, 64.3% (502/781) of MGH ICH survivors and 32.7% (128/391) of HKU had uncontrolled hypertension. Resistant hypertension accounted for 33.5% and 29.7% of uncontrolled hypertension in the respective cohorts, while the remaining patients qualified for the designation of inadequately medicated hypertension. Excluding patients with inadequately medicated hypertension, 60.0% of patients in MGH and 37.2% in HKU required ≥3 antihypertensive agents. Age 〈 65 years (odds ratio (OR) 1.80, p 〈 0.001), admission systolic BP of 〉 190 mmHg (OR 3.46, p 〈 0.001) and a history of hypertension before ICH (OR 3.39, p 〈 0.001) predicted the need for ≥3 antihypertensives after ICH. Conclusion: Medication inadequacy accounts for around two-thirds of uncontrolled hypertension after ICH, providing an opportunity for intervention to prevent hypertension-related complications, including ICH recurrence. As most ICH survivors required ≥3 antihypertensives for adequate BP control, early inpatient initiation of triple antihypertensive combination therapy should be considered, especially in patients with admission systolic BP of 〉 190 mmHg, known hypertension and aged 〈 65 years.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.51.suppl_1.15
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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