Orientational order parameters of a de Vries–type ferroelectric liquid crystal obtained by polarized Raman spectroscopy and x-ray diffraction

The orientational order parameters 〈P2〉 and 〈P4〉 of the ferroelectric, de Vries–type liquid crystal 9HL have been determined in the SmA* and SmC* phases by means of polarized Raman spectroscopy, and in the SmA* phase using x-ray diffraction. Quantum density functional theory predicts Raman spectra for 9HL that are in good agreement with the observations and indicates that the strong Raman band probed in the experiment corresponds to the uniaxial, coupled vibration of the three phenyl rings along the molecular long axis. The magnitudes of the orientational order parameters obtained in the Raman and x-ray experiments differ dramatically from each other, a discrepancy that is resolved by considering that the two techniques probe the orientational distributions of different molecular axes. We have developed a systematic procedure in which we calculate the angle between these axes and rescale the orientational order parameters obtained from x-ray scattering with results that are then in good agreement with the Raman data. At least in the case of 9HL, the results obtained by both techniques support a “sugar loaf” orientational distribution in the SmA* phase with no qualitative difference to conventional smectics A. The role of individual molecular fragments in promoting de Vries–type behavior is considered

Variants at APOE influence risk of deep and lobar intracerebral hemorrhage

Objective Prior studies investigating the association between APOE alleles ε2/ε4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for ε2 and ε4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results Alleles ε2 and ε4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50–2.23, p = 6.6 × 10 −10 ; and OR = 2.20, 95%CI = 1.85–2.63, p = 2.4 × 10 −11 , respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele ε4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08–1.36, p = 2.6 × 10 −4 ). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation APOE ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE ε4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78478/1/22134_ftp.pd

Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage

Background and Purpose-Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods-We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results-No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. Conclusion-Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. (Stroke. 2012; 43: 2877-2883.

Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.

OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. METHODS: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. RESULTS: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). CONCLUSIONS: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.Funding for collection, genotyping, and analysis of stroke samples was provided by Wellcome Trust Case Control Consortium-2, a functional genomics grant from the Wellcome Trust (DNA-Lacunar), the Stroke Association (DNA-lacunar), the Intramural Research Program of National Institute of Ageing (Massachusetts General Hospital [MGH] and Ischemic Stroke Genetics Study [ISGS]), National Institute of Neurological Disorders and Stroke (Siblings With Ischemic Stroke Study, ISGS, and MGH), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (MGH), Deane Institute for Integrative Study of Atrial Fibrillation and Stroke (MGH), National Health and Medical Research Council (Australian Stroke Genetics Collaborative), and Italian Ministry of Health (Milan). Additional support for sample collection came from the Medical Research Council, National Institute of Health Research Biomedical Research Centre and Acute Vascular Imaging Centre (Oxford), Wellcome Trust and Binks Trust (Edinburgh), and Vascular Dementia Research Foundation (Munich). MT is supported by a project grant from the Stroke Association (TSA 2013/01). HSM is supported by an NIHR Senior Investigator award. HSM and SB are supported by the NIHR Cambridge University Hospitals Comprehensive Biomedical Research Centre. VT and RL are supported by grants from FWO Flanders. PR holds NIHR and Wellcome Trust Senior Investigator Awards. PAS is supported by an MRC Fellowship. CML’s research is supported by the National Institute for Health Research Biomedical Research Centre (BRC) based at Guy's and St Thomas' NHS Foundation Trust and King's College London, and the BRC for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1212/WNL.000000000000226

Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10(-4) ) with no heterogeneity across studies (I(2) = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10(-6) ).INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740

Integrins AV and B8 Gene Polymorphisms and Risk for Intracerebral Hemorrhage in Greek and Polish Populations

Α limited number of genetic variants have been linked to the development of intracerebral hemorrhage (ICH). Ιntegrin AV and/or B8-deficient mice were found to develop ICH. The present candidate gene association study was designed to investigate possible influence of integrin AV (ITGAV) and integrin B8 (ITGB8) gene region polymorphisms on the risk of ICH. 1015 participants (250 Greek and 193 Polish patients with primary ICH and 250 Greek and 322 Polish controls) were included in the study. Using logistic regression analyses, 11 tag single nucleotide polymorphisms (SNPs) for ITGAV and 11 for ITGB8 gene were tested for associations with ICH risk, lobar ICH risk and non-lobar ICH after adjustment for age, gender, history of hypertension and country of origin. Linear regression models were used to test the effect of tag SNPs on the ICH age of onset. Correction for multiple comparisons was carried out. The rs7565633 tag SNP of the ITGAV gene was independently associated with the risk of lobar ICH in the codominant model of inheritance [odds ratio (95 % confidence interval (CI)) 0.56 (0.36–0.86), p = 0.0013]. Furthermore, heterozygous individuals of the rs10251386 and the rs10239099 of the ITGB8 gene had significantly lower age of ICH onset compared to the wild-type genotypes [regression coefficient (b) −3.884 (95 % CI −6.519, −1.249), p = 0.0039 and b = −4.502 (95 % CI −7.159, −1.845), p = 0.0009, respectively]. The present study provides preliminary indication for an influence of ITGAV gene tag SNP in the development of lobar ICH and of ITGB8 gene variants in the age of ICH onset. © 2016, Springer Science+Business Media New York

Integrins AV and B8 Gene Polymorphisms and Risk for Intracerebral Hemorrhage in Greek and Polish Populations

Α limited number of genetic variants have been linked to the development of intracerebral hemorrhage (ICH). Ιntegrin AV and/or B8-deficient mice were found to develop ICH. The present candidate gene association study was designed to investigate possible influence of integrin AV (ITGAV) and integrin B8 (ITGB8) gene region polymorphisms on the risk of ICH. 1015 participants (250 Greek and 193 Polish patients with primary ICH and 250 Greek and 322 Polish controls) were included in the study. Using logistic regression analyses, 11 tag single nucleotide polymorphisms (SNPs) for ITGAV and 11 for ITGB8 gene were tested for associations with ICH risk, lobar ICH risk and non-lobar ICH after adjustment for age, gender, history of hypertension and country of origin. Linear regression models were used to test the effect of tag SNPs on the ICH age of onset. Correction for multiple comparisons was carried out. The rs7565633 tag SNP of the ITGAV gene was independently associated with the risk of lobar ICH in the codominant model of inheritance [odds ratio (95 % confidence interval (CI)) 0.56 (0.36–0.86), p = 0.0013]. Furthermore, heterozygous individuals of the rs10251386 and the rs10239099 of the ITGB8 gene had significantly lower age of ICH onset compared to the wild-type genotypes [regression coefficient (b) −3.884 (95 % CI −6.519, −1.249), p = 0.0039 and b = −4.502 (95 % CI −7.159, −1.845), p = 0.0009, respectively]. The present study provides preliminary indication for an influence of ITGAV gene tag SNP in the development of lobar ICH and of ITGB8 gene variants in the age of ICH onset. © 2016, Springer Science+Business Media New York

AQP4 tag SNPs in patients with intracerebral hemorrhage in Greek and Polish population

Backround: A relatively small number of genetic variants are implicated to pathophysiology of intracerebral hemorrhage (ICH). Aquaporin-4 (AQP4) has been reported to be implicated in the pathophysiological processes of ICH development. Objective: To examine the role of AQP4 gene region polymorphisms on the ICH risk. Methods: A total of 250 Greek and 193 Polish patients with primary ICH and 250 and 322 respective controls were enrolled, forming two independent cohorts in order to validate any significant effect. With logistic regression analyses, 7 AQP4 tag single nucleotide polymorphisms (SNPs) were examined for association with ICH risk, lobar/non-lobar ICH risk, and 6-month disability after ICH. Cox regression analysis was applied in order to the effect of AQP4 SNPs on ICH age of onset be tested. Correction for multiple comparisons was applied. Results: Multivariate logistic regression analysis showed that rs3875089 in the Greek cohort and rs3763043, rs335931 in the Polish cohort had a significant influence on the risk of ICH, lobar and non-lobar ICH. Regarding the age of onset, rs3875089 in the Greek cohort and rs3763043, rs11661256 in the Polish cohort were found to significantly alter the age of onset of ICH and its subtypes. However, all of the above associations did not survive the Bonferroni correction (p-value >0.007). Finally, AQP4 tag SNPs were not found to have any significant effect on long-term disability after ICH. Conclusions: In conclusion, the present study provides an indication that AQP4 gene variants may affect susceptibility to primary ICH and may influence the ICH age of onset. © 2018 Elsevier B.V