Publications by authors named "Huichun Xu"

59 Publications

The burden of pathogenic variants in clinically actionable genes in a founder population.

Am J Med Genet A 2021 Nov 31;185(11):3476-3484. Epub 2021 Aug 31.

Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may be clinically actionable in 6136 apparently healthy adults living in the Lancaster, PA Old Order Amish settlement. We focused on variants in 78 genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger's MyCode Health Initiative. ES revealed 3191 total variants among these genes including 480 nonsynonymous variants. After quality control and filtering, we applied the ACMG/AMP guidelines for variant interpretation and classified seven variants, across seven genes, as either pathogenic or likely pathogenic. Through genetic drift, all seven variants, are highly enriched in the Amish compared to nonfounder populations. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. Other studies report combined frequencies of pathogenic/likely pathogenic (P/LP) variants in actionable genes between 2.0% and 6.2% in outbred populations. The Amish population harbors fewer actionable variants compared to similarly characterized nonfounder populations but have a higher frequency of each variant identified, offering opportunities for efficient and cost-effective targeted precision medicine.
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http://dx.doi.org/10.1002/ajmg.a.62472DOI Listing
November 2021

The copy number variation and stroke (CaNVAS) risk and outcome study.

PLoS One 2021 19;16(4):e0248791. Epub 2021 Apr 19.

University of Maryland School of Medicine, Baltimore, MD, United States of America.

Background And Purpose: The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap.

Methods: Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data.

Results: The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism.

Conclusion: The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055008PMC
September 2021

An Emerging Syndemic of Smoking and Cardiopulmonary Diseases in People Living with HIV in Africa.

Int J Environ Res Public Health 2021 03 18;18(6). Epub 2021 Mar 18.

Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY 10029, USA.

Background: African countries have the highest number of people living with HIV (PWH). The continent is home to 12% of the global population, but accounts for 71% of PWH globally. Antiretroviral therapy has played an important role in the reduction of the morbidity and mortality rates for HIV, which necessitates increased surveillance of the threats from pernicious risks to which PWH who live longer remain exposed. This includes cardiopulmonary comorbidities, which pose significant public health and economic challenges. A significant contributor to the cardiopulmonary comorbidities is tobacco smoking. Indeed, globally, PWH have a 2-4-fold higher utilization of tobacco compared to the general population, leading to endothelial dysfunction and atherogenesis that result in cardiopulmonary diseases, such as chronic obstructive pulmonary disease and coronary artery disease. In the context of PWH, we discuss (1) the current trends in cigarette smoking and (2) the lack of geographically relevant data on the cardiopulmonary conditions associated with smoking; we then review (3) the current evidence on chronic inflammation induced by smoking and the potential pathways for cardiopulmonary disease and (4) the multifactorial nature of the syndemic of smoking, HIV, and cardiopulmonary diseases. This commentary calls for a major, multi-setting cohort study using a syndemics framework to assess cardiopulmonary disease outcomes among PWH who smoke.

Conclusion: We call for a parallel program of implementation research to promote the adoption of evidence-based interventions, which could improve health outcomes for PWH with cardiopulmonary diseases and address the health inequities experienced by PWH in African countries.
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http://dx.doi.org/10.3390/ijerph18063111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003038PMC
March 2021

Exome Array Analysis of Early-Onset Ischemic Stroke.

Stroke 2020 11 11;51(11):3356-3360. Epub 2020 Sep 11.

University of Maryland School of Medicine, Baltimore, MD (T.J., K.A.R., B.J.G., P.F.M., O.C.S., T.D.O., H.L., S.J.K., B.D.M., H.X., J.W.C.).

Background And Purpose: The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease.

Methods: Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases.

Results: Gene burden tests identified a significant association with in small-vessel stroke (=3.79×10). Pathway analysis of the top 517 genes (<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (<2.05×10), several were near, including an intronic variant in (rs7549251; =4.08×10) and an exonic variant in (rs67383011; =5.19×10).

Conclusions: Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.
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http://dx.doi.org/10.1161/STROKEAHA.120.031357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606344PMC
November 2020

Diffusion-Weighted Imaging, MR Angiography, and Baseline Data in a Systematic Multicenter Analysis of 3,301 MRI Scans of Ischemic Stroke Patients-Neuroradiological Review Within the MRI-GENIE Study.

Front Neurol 2020 25;11:577. Epub 2020 Jun 25.

Department of Neurology and the Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, United States.

Magnetic resonance imaging (MRI) serves as a cornerstone in defining stroke phenotype and etiological subtype through examination of ischemic stroke lesion appearance and is therefore an essential tool in linking genetic traits and stroke. Building on baseline MRI examinations from the centralized and structured radiological assessments of ischemic stroke patients in the Stroke Genetics Network, the results of the MRI-Genetics Interface Exploration (MRI-GENIE) study are described in this work. The MRI-GENIE study included patients with symptoms caused by ischemic stroke ( = 3,301) from 12 international centers. We established and used a structured reporting protocol for all assessments. Two neuroradiologists, using a blinded evaluation protocol, independently reviewed the baseline diffusion-weighted images (DWIs) and magnetic resonance angiography images to determine acute lesion and vascular occlusion characteristics. In this systematic multicenter radiological analysis of clinical MRI from 3,301 acute ischemic stroke patients according to a structured prespecified protocol, we identified that anterior circulation infarcts were most prevalent (67.4%), that infarcts in the middle cerebral artery (MCA) territory were the most common, and that the majority of large artery occlusions 0 to 48 h from ictus were in the MCA territory. Multiple acute lesions in one or several vascular territories were common (11%). Of 2,238 patients with unilateral DWI lesions, 52.6% had left-sided infarct lateralization ( = 0.013 for χ test). This large-scale analysis of a multicenter MRI-based cohort of AIS patients presents a unique imaging framework facilitating the relationship between imaging and genetics for advancing the knowledge of genetic traits linked to ischemic stroke.
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http://dx.doi.org/10.3389/fneur.2020.00577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330135PMC
June 2020

White matter hyperintensity burden in acute stroke patients differs by ischemic stroke subtype.

Neurology 2020 07 3;95(1):e79-e88. Epub 2020 Jun 3.

From the Department of Neurology (A.-K.G., M.D.S., K.L.D., M.N., J.R., O.W., N.S.R.), Massachusetts General Hospital, Harvard Medical School, Boston; Program in Medical and Population Genetics (A.K.-G, J.R.), Broad Institute of MIT and Harvard; Computer Science and Artificial Intelligence Lab (M.D.S., A.V.D., R. Sridharan, P.G.), Massachusetts Institute of Technology, Cambridge; Department of Population Health Sciences (M.D.S.), German Centre for Neurodegenerative Diseases, Bonn, Germany; Athinoula A. Martinos Center for Biomedical Imaging (A.V.D., R.I., E.C.M., S.J.T.M., J.R., O.W.), Department of Radiology, Massachusetts General Hospital, Charlestown; Division of Endocrinology, Diabetes and Nutrition (H.X., P.F.M., B.D.M.), Department of Medicine, University of Maryland School of Medicine; Department of Neurology (J.W.C., S.J.K.), University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore; Department of Neurology (E.G.-S., J.J.-C.), Neurovascular Research Group, IMIM-Hospital del Mar (Institut Hospital del Mar d'Investigacions Mèdiques), Universitat Autonoma de Barcelona, Spain; Institute of Biomedicine (C.J.), Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Neurology and Rehabilitation Medicine (D.O.K., D.W.), University of Cincinnati College of Medicine, OH; KU Leuven-University of Leuven (R.L.), Department of Neurosciences, Experimental Neurology; VIB (R.L.), Vesalius Research Center, Laboratory of Neurobiology, University Hospitals Leuven, Department of Neurology, Belgium; Department of Clinical Sciences Lund (J.W., A.L.), Neurology, Lund University; Department of Neurology and Rehabilitation Medicine (A.L.), Neurology, Skåne University Hospital, Lund, Sweden; Department of Neurology (T.R., R.L.S.), Miller School of Medicine, University of Miami, The Evelyn F. McKnight Brain Institute, FL; Department of Neurology (R. Schmidt), Clinical Division of Neurogeriatrics, Medical University Graz, Austria; Institute of Cardiovascular Research (P.S.), Royal Holloway University of London, Egham, UK; Ashford and St Peter's Hospital (P.S.), UK; Department of Neurology (A.S.), Jagiellonian University Medical College, Krakow, Poland; Stroke Division (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne Heidelberg; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia, Charlottesville; Center for Genomic Medicine (J.R.), Massachusetts General Hospital; Henry and Allison McCance Center for Brain Health (J.R.), Boston, MA; and Department of Neurology (J.F.M.), Mayo Clinic, Jacksonville, FL.

Objective: To examine etiologic stroke subtypes and vascular risk factor profiles and their association with white matter hyperintensity (WMH) burden in patients hospitalized for acute ischemic stroke (AIS).

Methods: For the MRI Genetics Interface Exploration (MRI-GENIE) study, we systematically assembled brain imaging and phenotypic data for 3,301 patients with AIS. All cases underwent standardized web tool-based stroke subtyping with the Causative Classification of Ischemic Stroke (CCS). WMH volume (WMHv) was measured on T2 brain MRI scans of 2,529 patients with a fully automated deep-learning trained algorithm. Univariable and multivariable linear mixed-effects modeling was carried out to investigate the relationship of vascular risk factors with WMHv and CCS subtypes.

Results: Patients with AIS with large artery atherosclerosis, major cardioembolic stroke, small artery occlusion (SAO), other, and undetermined causes of AIS differed significantly in their vascular risk factor profile (all < 0.001). Median WMHv in all patients with AIS was 5.86 cm (interquartile range 2.18-14.61 cm) and differed significantly across CCS subtypes ( < 0.0001). In multivariable analysis, age, hypertension, prior stroke, smoking (all < 0.001), and diabetes mellitus ( = 0.041) were independent predictors of WMHv. When adjusted for confounders, patients with SAO had significantly higher WMHv compared to those with all other stroke subtypes ( < 0.001).

Conclusion: In this international multicenter, hospital-based cohort of patients with AIS, we demonstrate that vascular risk factor profiles and extent of WMH burden differ by CCS subtype, with the highest lesion burden detected in patients with SAO. These findings further support the small vessel hypothesis of WMH lesions detected on brain MRI of patients with ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000009728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371377PMC
July 2020

Methods for an Investigation of Neurophysiological and Kinematic Predictors of Response to Upper Extremity Repetitive Task Practice in Chronic Stroke.

Arch Rehabil Res Clin Transl 2019 Dec 10;1(3-4). Epub 2019 Sep 10.

VA Maryland Health Care System, Baltimore VA Medical Center, Baltimore, Maryland.

Objective: To demonstrate the feasibility of algorithmic prediction using a model of baseline arm movement, genetic factors, demographic characteristics, and multimodal assessment of the structure and function of motor pathways. To identify prognostic factors and the biological substrate for reductions in arm impairment in response to repetitive task practice.

Design: This prospective single-group interventional study seeks to predict response to a repetitive task practice program using an intent-to-treat paradigm. Response is measured as a change of ≥5 points on the Upper Extremity Fugl-Meyer from baseline to final evaluation (at the end of training).

Setting: General community.

Participants: Anticipated enrollment of community-dwelling adults with chronic stroke (N = 96; onset≥6mo) and moderate to severe residual hemiparesis of the upper limb as defined by a score of 10-45 points on the Upper Extremity Fugl-Meyer.

Intervention: The intervention is a form of repetitive task practice using a combination of robot-assisted therapy coupled with functional arm use in real-world tasks administered over 12 weeks.

Main Outcome Measures: Upper Extremity Fugl-Meyer Assessment (primary outcome), Wolf Motor Function Test, Action Research Arm Test, Stroke Impact Scale, questionnaires on pain and expectancy, magnetic resonance imaging, transcranial magnetic stimulation, arm kinematics, accelerometry, and a saliva sample for genetic testing.

Results: Methods for this trial are outlined, and an illustration of interindividual variability is provided by example of 2 participants who present similarly at baseline but achieve markedly different outcomes.

Conclusion: This article presents the design, methodology, and rationale of an ongoing study to develop a predictive model of response to a standardized therapy for stroke survivors with chronic hemiparesis. Applying concepts from precision medicine to neurorehabilitation is practicable and needed to establish realistic rehabilitation goals and to effectively allocate resources.
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http://dx.doi.org/10.1016/j.arrct.2019.100024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155389PMC
December 2019

mRNA Expression Profiles from Whole Blood Associated with Vasospasm in Patients with Subarachnoid Hemorrhage.

Neurocrit Care 2020 08;33(1):82-89

Department of Neurology, University of California at San Francisco, San Francisco, USA.

Background: Though there are many biomarker studies of plasma and serum in patients with aneurysmal subarachnoid hemorrhage (SAH), few have examined blood cells that might contribute to vasospasm. In this study, we evaluated inflammatory and prothrombotic pathways by examining mRNA expression in whole blood of SAH patients with and without vasospasm.

Methods: Adult SAH patients with vasospasm (n = 29) and without vasospasm (n = 21) were matched for sex, race/ethnicity, and aneurysm treatment method. Diagnosis of vasospasm was made by angiography. mRNA expression was measured by Affymetrix Human Exon 1.0 ST Arrays. SAH patients with vasospasm were compared to those without vasospasm by ANCOVA to identify differential gene, exon, and alternatively spliced transcript expression. Analyses were adjusted for age, batch, and time of blood draw after SAH.

Results: At the gene level, there were 259 differentially expressed genes between SAH patients with vasospasm compared to patients without (false discovery rate < 0.05, |fold change| ≥ 1.2). At the exon level, 1210 exons representing 1093 genes were differentially regulated between the two groups (P < 0.005, ≥ 1.2 |fold change|). Principal components analysis segregated SAH patients with and without vasospasm. Signaling pathways for the 1093 vasospasm-related genes included adrenergic, P2Y, ET-1, NO, sildenafil, renin-angiotensin, thrombin, CCR3, CXCR4, MIF, fMLP, PKA, PKC, CRH, PPARα/RXRα, and calcium. Genes predicted to be alternatively spliced included IL23A, RSU1, PAQR6, and TRIP6.

Conclusions: This is the first study to demonstrate that mRNA expression in whole blood distinguishes SAH patients with vasospasm from those without vasospasm and supports a role of coagulation and immune systems in vasospasm.
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http://dx.doi.org/10.1007/s12028-019-00861-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392923PMC
August 2020

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.

Am J Hum Genet 2019 10 26;105(4):706-718. Epub 2019 Sep 26.

National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham MA 01702, USA; Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (-0.88% in hemizygous males, -0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; -0.98% in hemizygous males, -0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.
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http://dx.doi.org/10.1016/j.ajhg.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817529PMC
October 2019

Self-Reported Sleep Duration and Pattern in Old Order Amish and Non-Amish Adults.

J Clin Sleep Med 2019 09;15(9):1321-1328

Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.

Study Objectives: We hypothesized that sleep duration in the Amish would be longer than in non-Amish.

Methods: Sleep duration was obtained by questionnaire administered to Amish individuals (n = 3,418) and from the 2015-2016 National Health and Nutrition Examination Survey (NHANES; n = 1,912). Self-reported sleep duration was calculated as the difference in usual times that the participants went to bed at night and woke up in the morning.

Results: In Amish (43.7 ± 16.7 years) and NHANES (50.0 ± 20.6 years), women had a longer sleep duration than men (P < .0001 in both groups) and sleep was significantly longer in those aged 18-29 years and ≥ 70 years, compared to those aged 30-69 years. Seasonal-adjusted sleep duration was shorter in Amish than that in NHANES (7.8 minutes shorter, age- and sex-adjusted P < .0001). However, Amish were less likely to report sleeping fewer than 7 hours per night (15.4% in Amish versus 20.5% in NHANES, P < .0001). Amish went to bed 80.4 minutes earlier than NHANES and arose 87.6 minutes earlier (age-, sex-, and season-adjusted P < .0001 for both). In the Amish, sleep duration was longer in clerks than in farmers (P < .0001) and was significantly correlated among household members (.15 < r < .62, P < .001), although there was no evidence that this trait was heritable (h² approximately 0) after adjustment for household.

Conclusions: The lower frequency of short sleepers in the Amish may contribute to the relatively lower risks of cardiometabolic diseases observed in this population.

Citation: Zhang M, Ryan KA, Wickwire E, Postolache TT, Xu H, Daue M, Snitker S, Pollin TI, Shuldiner AR, Mitchell BD. Self-reported sleep duration and pattern in old order amish and non-amish adults. J Clin Sleep Med. 2019;15(9):1321-1328.
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http://dx.doi.org/10.5664/jcsm.7928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760415PMC
September 2019

Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls.

Circ Genom Precis Med 2019 07 15;12(7):e002338. Epub 2019 Jul 15.

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München (M.D., R.M.).

Background: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes.

Methods: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel.

Results: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes.

Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.
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http://dx.doi.org/10.1161/CIRCGEN.118.002338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477820PMC
July 2019

White matter hyperintensity quantification in large-scale clinical acute ischemic stroke cohorts - The MRI-GENIE study.

Neuroimage Clin 2019 29;23:101884. Epub 2019 May 29.

Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.
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http://dx.doi.org/10.1016/j.nicl.2019.101884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562316PMC
June 2020

Brain-derived neurotrophic factor, epigenetics in stroke skeletal muscle, and exercise training.

Neurol Genet 2019 Jun 1;5(3):e331. Epub 2019 May 1.

VA Maryland Health Care System, Research Service, Department of Medicine, Division of Gerontology and Geriatric Medicine, Department of Neurology, at the University of Maryland School of Medicine, and the Baltimore Geriatric Research, Education and Clinical Center (GRECC), MD.

Objective: (1) To compare paretic (P) vs nonparetic (NP) skeletal muscle brain-derived neurotrophic factor (BDNF) and the effects of resistive training (RT) on systemic and skeletal muscle BDNF mRNA expression in stroke; and (2) to compare the DNA methylation profile for BDNF and BDNFAS (BDNF antisense RNA) between P and NP muscle and the effects of aerobic exercise training (AEX) on DNA methylation in stroke.

Methods: In this longitudinal investigation, participants (50-76 years) with chronic stroke underwent a fasting blood draw, a 12-week (3×/week) RT intervention (n = 16), and repeated bilateral vastus lateralis muscle tissue biopsies (n = 10) with BDNF expression determined by RT-PCR. Five stroke survivors completed 6 months of AEX (3×/week) and had bilateral muscle biopsies. DNA methylation status in gene BDNF and BDNFAS was assessed by Illumina 450k methylation array.

Results: P muscle had ∼45% lower BDNF mRNA expression than NP muscle (6.79 ± 1.30 vs 10.52 ± 2.06 arbitrary units [AU], < 0.05), and P muscle exhibited differential methylation status in the DNA sequences of BDNF (3 CpG [5'-C-phosphate-G-3'] sites, = 0.016-0.044) and BDNFAS (1 CpG site, = 0.016) compared to NP. Plasma BDNF and muscle BDNF messenger RNA (mRNA) expression did not significantly change after RT. BDNFAS DNA methylation increased after AEX in P relative to NP muscle ( = 0.017).

Conclusions: This is the first evidence that stroke hemiparesis reduces BDNF skeletal muscle expression, with our findings identifying methylation alterations on the DNA sequence of BDNF and BDNFAS gene. Preliminary results further indicate that AEX increases methylation in BDNFAS gene, which presumably could regulate the expression of BDNF.
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http://dx.doi.org/10.1212/NXG.0000000000000331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515940PMC
June 2019

Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data.

Stroke 2019 07 10;50(7):1734-1741. Epub 2019 Jun 10.

Department of Laboratory Medicine, Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden (E.L., T.M.S., C.J.).

Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm (0.9-16.6 cm). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.
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http://dx.doi.org/10.1161/STROKEAHA.119.025373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728139PMC
July 2019

Increased usual physical activity is associated with a blunting of the triglyceride response to a high-fat meal.

J Clin Lipidol 2019 Jan - Feb;13(1):109-114. Epub 2018 Nov 20.

Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

Background: Postprandial lipemia (PPL), defined as a prolonged or elevated rise in triglycerides that accompanies fat feeding, is a significant risk factor for coronary heart disease and associated comorbidities. The impact of PPL on coronary heart disease risk is underscored by the preponderance of each day spent in the postprandial state.

Objective: In this study, we evaluated cross-sectionally the association between usual (ie, noninterventional) physical activity and the 6-hour triglyceride response to a standardized high-fat meal.

Methods: The high-fat meal intervention was carried out in 671 apparently healthy individuals as part of the Heredity and Phenotype Intervention Heart Study. Triglyceride levels were measured in the fasting state and during 6 hours after administration of a standardized fat challenge. We defined PPL response as the triglyceride area under the fat load curve (AUC) and measured physical activity using accelerometers that were worn continuously over a 7-day period.

Results: Physical activity levels decreased with increasing age and were higher in men than women (both P < .001). The triglyceride AUC increased with increasing age in both men and women (both P < .001) and was also higher in men than in women (age-adjusted P = 9.2 × 10). Higher physical activity levels were associated with a lower triglyceride AUC (P = .003), adjusting for age, sex, body mass index, and fasting low-density lipoprotein.

Conclusion: These results suggest that the protective benefits of physical activity on cardiovascular health may operate, at least in part, through reduction of the PPL triglyceride response.
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http://dx.doi.org/10.1016/j.jacl.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379118PMC
May 2020

Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke.

PLoS One 2018 1;13(11):e0206554. Epub 2018 Nov 1.

University of Adelaide, Adelaide, Australia.

Background And Purpose: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication.

Methods: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base.

Results: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity.

Conclusion: PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211695PMC
April 2019

A Genome-Wide Association Study of Idiopathic Dilated Cardiomyopathy in African Americans.

J Pers Med 2018 02 26;8(1). Epub 2018 Feb 26.

Department of Internal Medicine and Molecular Pharmacology and Physiology, and the Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.

Idiopathic dilated cardiomyopathy (IDC) is the most common form of non-ischemic chronic heart failure. Despite the higher prevalence of IDC in African Americans, the genetics of IDC have been relatively understudied in this ethnic group. We performed a genome-wide association study to identify susceptibility genes for IDC in African Americans recruited from five sites in the U.S. (662 unrelated cases and 1167 controls). The heritability of IDC was calculated to be 33% (95% confidence interval: 19-47%; = 6.4 × 10). We detected association of a variant in a novel intronic locus in the gene meeting genome-wide levels of significance ( = 4.1 × 10). The gene encodes a calcium channel subunit expressed in the heart that is important for cardiac muscle contraction. This variant has not previously been associated with IDC in any racial group. Pathway analysis, based on the 1000 genes most strongly associated with IDC, showed an enrichment for genes related to calcium signaling, growth factor signaling, neuronal/neuromuscular signaling, and various types of cellular level signaling, including gap junction and cAMP signaling. Our results suggest a novel locus for IDC in African Americans and provide additional insights into the genetic architecture and etiology.
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http://dx.doi.org/10.3390/jpm8010011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872085PMC
February 2018

Polygenic Risk for Depression Increases Risk of Ischemic Stroke: From the Stroke Genetics Network Study.

Stroke 2018 03 8;49(3):543-548. Epub 2018 Feb 8.

From the Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (S.W.-S., Q.Q.); University of Maryland School of Medicine, Baltimore (T.D., B.D.M., H.X., K.R.); Department of Medicine, Ohio State University, Columbus (R.D.J.); Department of Epidemiology (S.L.) and Department of Medicine (S.L.), Brown School of Public Health and Alpert Medical School, Providence, RI; Division of Cardiology, University of Florida, Gainesville (K.P.); Department of Neurology (J.S.) and Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Center for Genomic Medicine (E.C.D., J.W.S.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Neurology, Carver College of Medicine (E.C.L.) and Department of Epidemiology, College of Public Health (E.C.L.), University of Iowa, Iowa City.

Background And Purpose: Although depression is a risk factor for stroke in large prospective studies, it is unknown whether these conditions have a shared genetic basis.

Methods: We applied a polygenic risk score (PRS) for major depressive disorder derived from European ancestry analyses by the Psychiatric Genomics Consortium to a genome-wide association study of ischemic stroke in the Stroke Genetics Network of National Institute of Neurological Disorders and Stroke. Included in separate analyses were 12 577 stroke cases and 25 643 controls of European ancestry and 1353 cases and 2383 controls of African ancestry. We examined the association between depression PRS and ischemic stroke overall and with pathogenic subtypes using logistic regression analyses.

Results: The depression PRS was associated with higher risk of ischemic stroke overall in both European (=0.025) and African ancestry (=0.011) samples from the Stroke Genetics Network. Ischemic stroke risk increased by 3.0% (odds ratio, 1.03; 95% confidence interval, 1.00-1.05) for every 1 SD increase in PRS for those of European ancestry and by 8% (odds ratio, 1.08; 95% confidence interval, 1.04-1.13) for those of African ancestry. Among stroke subtypes, elevated risk of small artery occlusion was observed in both European and African ancestry samples. Depression PRS was also associated with higher risk of cardioembolic stroke in European ancestry and large artery atherosclerosis in African ancestry persons.

Conclusions: Higher polygenic risk for major depressive disorder is associated with increased risk of ischemic stroke overall and with small artery occlusion. Additional associations with ischemic stroke subtypes differed by ancestry.
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http://dx.doi.org/10.1161/STROKEAHA.117.018857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909718PMC
March 2018

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

J Neurol Sci 2017 Nov 18;382:18-28. Epub 2017 Sep 18.

Department of Neurology, Medical University of South Carolina, Charleston, USA.

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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http://dx.doi.org/10.1016/j.jns.2017.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685670PMC
November 2017

Design and rationale for examining neuroimaging genetics in ischemic stroke: The MRI-GENIE study.

Neurol Genet 2017 Oct 24;3(5):e180. Epub 2017 Aug 24.

Author affiliations are provided at the end of the article.

Objective: To describe the design and rationale for the genetic analysis of acute and chronic cerebrovascular neuroimaging phenotypes detected on clinical MRI in patients with acute ischemic stroke (AIS) within the scope of the MRI-GENetics Interface Exploration (MRI-GENIE) study.

Methods: MRI-GENIE capitalizes on the existing infrastructure of the Stroke Genetics Network (SiGN). In total, 12 international SiGN sites contributed MRIs of 3,301 patients with AIS. Detailed clinical phenotyping with the web-based Causative Classification of Stroke (CCS) system and genome-wide genotyping data were available for all participants. Neuroimaging analyses include the manual and automated assessments of established MRI markers. A high-throughput MRI analysis pipeline for the automated assessment of cerebrovascular lesions on clinical scans will be developed in a subset of scans for both acute and chronic lesions, validated against gold standard, and applied to all available scans. The extracted neuroimaging phenotypes will improve characterization of acute and chronic cerebrovascular lesions in ischemic stroke, including CCS subtypes, and their effect on functional outcomes after stroke. Moreover, genetic testing will uncover variants associated with acute and chronic MRI manifestations of cerebrovascular disease.

Conclusions: The MRI-GENIE study aims to develop, validate, and distribute the MRI analysis platform for scans acquired as part of clinical care for patients with AIS, which will lead to (1) novel genetic discoveries in ischemic stroke, (2) strategies for personalized stroke risk assessment, and (3) personalized stroke outcome assessment.
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http://dx.doi.org/10.1212/NXG.0000000000000180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570675PMC
October 2017

Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish.

Diabetes 2017 07 20;66(7):2054-2058. Epub 2017 Apr 20.

Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD

Alleles associated with lower levels of LDL cholesterol (LDL-C) have recently been associated with an increased risk of type 2 diabetes (T2D), highlighting the complex relationship between LDL-C and diabetes. This observation begs the question of whether LDL-C-raising alleles are associated with a decreased risk of T2D. This issue was recently addressed in a large familial hypercholesterolemia (FH) screening study, which reported a lower prevalence of self-reported diabetes in FH subjects than in age-matched relatives without FH. To extend this observation, we tested the association of FH with diabetes status and glycemia in a large Amish population enriched for the FH-associated R3527Q variant that included 640 R3527Q carriers and 4,683 noncarriers. Each copy of the R3527Q T allele was associated with a 74.9 mg/dL increase in LDL-C. There was little difference in T2D prevalence between subjects with (5.2%) and without (4.5%) the R3527Q allele ( = 0.23), and there was no association between R3527Q variant and impaired fasting glucose, fasting glucose or insulin, or oral glucose tolerance test-derived measures. Our data provide no evidence supporting an association between the R3527Q variant and T2D or glycemia and highlight the asymmetry of the LDL-C-T2D relationship and/or the gene/variant-dependent specificity of the LDL-C-T2D association.
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http://dx.doi.org/10.2337/db17-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482078PMC
July 2017

and Loci Associate with Plasma Osmolality.

J Am Soc Nephrol 2017 Aug 30;28(8):2311-2321. Epub 2017 Mar 30.

Due to the number of contributing authors, the affiliations are listed in the supplemental material.

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at <5.0 × 10 Of these, rs9980 at replicated in stage 2 meta-analysis (=3.1 × 10), with combined stages 1 and 2 genome-wide significance of =5.6 × 10 Transethnic meta-analysis further supported the association at rs9980 (=5.9 × 10). Additionally, rs16846053 at showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (=6.7 × 10). encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for and are expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in and expression and function in the central nervous system may affect the regulation of systemic water balance.
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http://dx.doi.org/10.1681/ASN.2016080892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533231PMC
August 2017

The Importance of Conducting Stroke Genomics Research in African Ancestry Populations.

Glob Heart 2017 06 20;12(2):163-168. Epub 2017 Mar 20.

Department of Neurology, Veterans Affairs Maryland Health Care System, Baltimore, MD, USA; Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1016/j.gheart.2017.01.004DOI Listing
June 2017

Genetic variation at 16q24.2 is associated with small vessel stroke.

Ann Neurol 2017 Mar;81(3):383-394

Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.

Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke.

Methods: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.

Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10 ).

Interpretation: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.
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http://dx.doi.org/10.1002/ana.24840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366092PMC
March 2017

A Deep Proteome Analysis Identifies the Complete Secretome as the Functional Unit of Human Cardiac Progenitor Cells.

Circ Res 2017 Mar 1;120(5):816-834. Epub 2016 Dec 1.

From the Division of Cardiac Surgery, School of Medicine (S.S., R.M., G.E.B., B.W., P.S., S.R.D., B.S.T., S.K.), Department of Pharmaceutical Sciences, School of Pharmacy (M.M.K., Y.A.G., D.R.G.), Division of Endocrinology, Diabetes and Nutrition, Department of Medicine (H.X.), Department of Physiology and Medicine, School of Medicine (L.C.), Department of OB/GYN & Reproductive Science, Department of Biochemistry and Molecular Biology, School of Medicine (P.Y.), and Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine (M.E.T.), University of Maryland, Baltimore; and Cardiovascular and Metabolic Diseases, Innovative Medicines Biotech Unit MedImmune, Inc., Gaithersburg, MD (S.K.).

Rationale: Cardiac progenitor cells are an attractive cell type for tissue regeneration, but their mechanism for myocardial remodeling is still unclear.

Objective: This investigation determines how chronological age influences the phenotypic characteristics and the secretome of human cardiac progenitor cells (CPCs), and their potential to recover injured myocardium.

Methods And Results: Adult (aCPCs) and neonatal (nCPCs) cells were derived from patients aged >40 years or <1 month, respectively, and their functional potential was determined in a rodent myocardial infarction model. A more robust in vitro proliferative capacity of nCPCs, compared with aCPCs, correlated with significantly greater myocardial recovery mediated by nCPCs in vivo. Strikingly, a single injection of nCPC-derived total conditioned media was significantly more effective than nCPCs, aCPC-derived TCM, or nCPC-derived exosomes in recovering cardiac function, stimulating neovascularization, and promoting myocardial remodeling. High-resolution accurate mass spectrometry with reverse phase liquid chromatography fractionation and mass spectrometry was used to identify proteins in the secretome of aCPCs and nCPCs, and the literature-based networking software identified specific pathways affected by the secretome of CPCs in the setting of myocardial infarction. Examining the TCM, we quantified changes in the expression pattern of 804 proteins in nCPC-derived TCM and 513 proteins in aCPC-derived TCM. The literature-based proteomic network analysis identified that 46 and 6 canonical signaling pathways were significantly targeted by nCPC-derived TCM and aCPC-derived TCM, respectively. One leading candidate pathway is heat-shock factor-1, potentially affecting 8 identified pathways for nCPC-derived TCM but none for aCPC-derived TCM. To validate this prediction, we demonstrated that the modulation of heat-shock factor-1 by knockdown in nCPCs or overexpression in aCPCs significantly altered the quality of their secretome.

Conclusions: A deep proteomic analysis revealed both detailed and global mechanisms underlying the chronological age-based differences in the ability of CPCs to promote myocardial recovery via the components of their secretome.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.309782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834230PMC
March 2017

Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study.

J Am Soc Nephrol 2017 Mar 11;28(3):923-934. Epub 2016 Oct 11.

Division of Intramural Research, National Heart, Lung and Blood Institute's Framingham Heart Study, National Heart, Lung and Blood Institute, Framingham, Massachusetts.

The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of <1×10 for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in replicated in the African American Study of Kidney Disease and Hypertension cohort (discovery =5.42×10; replication =0.039; combined =7.42×10). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); =4.90×10). Similarly, rs931891 in associated with eGFR decline (=1.44×10) in white patients without diabetes. In summary, SNPs in , an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted.
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http://dx.doi.org/10.1681/ASN.2015101152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328149PMC
March 2017

Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.

Stroke 2016 Feb 5;47(2):307-16. Epub 2016 Jan 5.

From the Veterans Affairs Maryland Health Care System, Baltimore, MD (Y.-C.C., S.J.K., J.W.C., B.D.M.); University of Maryland School of Medicine, Baltimore (Y.-C.C., H.X., S.J.K., J.W.C., J.R.O., B.D.M.); The University of Gothenburg, Gothenburg, Sweden (T.M.S., C.J.); University of Rostock, Rostock, Germany (A.-K.G., A. Rolfs); University of Nottingham Malaysia Campus, Selangor Darul Ehsa, Malaysia (W.K.H.); University of Cambridge, Cambridge, UK (M.T., J.D., S.B., H.S.M., S.D., D.S.); Institut Pasteur de Lille, F-59000 Lille, France (P.A.); University of Newcastle, Australia (E.G.H.); Ludwig-Maximilians-Universität, Munich, Germany (R.M., K.S., M.D.); Wellcome Trust Sanger Institute, Cambridge, UK (J.D.); Center for Non-Communicable Diseases, Karachi, Pakistan (A. Rasheed, D.S.); University of Pennsylvania (W.Z., D.S.); Basel University Hospital, Switzerland (S.E.); Heidelberg University Hospital, Germany (C.G.-G.); Centre d'Étude du Polymorphisme Humain, Paris, France (Y.K.); RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (Y.K.); National Genotyping Center, Evry, France (M.L.); Genome Quebec, McGill University, Montreal, Canada (M.L.); Lille University Hospital, France (D.L., S.D.); KU Leuven - University of Leuven, Leuven, Belgium (V.T.); Vesalius Research Center, VIB, Leuven, Belgium (V.T.); University Hospitals Leuven, Leuven, Belgium (V.T.); Helsinki University Central Hospital, Helsinki, Finland (T.M.M., T.T.); Università degli Studi di Brescia, Brescia, Italy (A. Pezzini); Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy (E.A.P., G.B.B.); University of Lund, Sweden (B.N.); University of Oxford, John Radcliffe Hospital (P.M.R.); University of Edinburgh, Edinburgh, UK (C.S.); Jagiellonian University Medical College, Krakow, Poland (A.S.); Lund University, Lund, Sweden (A.L.); Skåne University Hospital, Lund, Sweden (A.L.); University of Glasgow, Glasgow, UK (M.R.W.); University of Adelaide, Australia (J.J.); Mount Sinai Hos

Background And Purpose: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

Methods: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.

Results: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

Conclusions: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
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http://dx.doi.org/10.1161/STROKEAHA.115.011328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729659PMC
February 2016

Global Gene Expression Profiling in Omental Adipose Tissue of Morbidly Obese Diabetic African Americans.

J Endocrinol Metab 2015 Jun;5(3):199-210

Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.

Background: Adipose tissues play important role in the pathophysiology of obesity-related diseases including type 2 diabetes (T2D). To describe gene expression patterns and functional pathways in obesity-related T2D, we performed global transcript profiling of omental adipose tissue (OAT) in morbidly obese individuals with or without T2D.

Methods: Twenty morbidly obese (mean BMI: about 54 kg/m) subjects were studied, including 14 morbidly obese individuals with T2D (cases) and 6 morbidly obese individuals without T2D (reference group). Gene expression profiling was performed using the Affymetrix U133 Plus 2.0 human genome expression array. Analysis of covariance was performed to identify differentially expressed genes (DEGs). Bioinformatics tools including PANTHER and Ingenuity Pathway Analysis (IPA) were applied to the DEGs to determine biological functions, networks and canonical pathways that were overrepresented in these individuals.

Results: At an absolute fold-change threshold of 2 and false discovery rate (FDR) < 0.05, 68 DEGs were identified in cases compared to the reference group. Myosin X (MYO10) and transforming growth factor beta regulator 1 (TBRG1) were upregulated. encodes for an actin-based motor protein that has been associated with T2D. Telomere extension by telomerase (), D-myo-inositol (1, 4, 5)-trisphosphate biosynthesis (PIP5K1A, PIP4K2A), and regulation of actin-based motility by Rho (ARPC3) were the most significant canonical pathways and overlay with T2D signaling pathway. Upstream regulator analysis predicted 5 miRNAs (miR-320b, miR-381-3p, miR-3679-3p, miR-494-3p, and miR-141-3p,) as regulators of the expression changes identified.

Conclusion: This study identified a number of transcripts and miRNAs in OAT as candidate novel players in the pathophysiology of T2D in African Americans.
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http://dx.doi.org/10.14740/jem286wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618674PMC
June 2015

Aryl Hydrocarbon Receptor Repressor Methylation: A Link Between Smoking and Atherosclerosis.

Circ Cardiovasc Genet 2015 Oct;8(5):640-2

From the Department of Neurology, Maryland Stroke Center, University of Maryland School of Medicine, Baltimore (J.W.C.); Department of Neurology, Baltimore VA Medical Center, Baltimore (J.W.C.); and Division of Endocrinology, Department of Medicine, University of Maryland School of Medicine, Baltimore (H.X.).

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http://dx.doi.org/10.1161/CIRCGENETICS.115.001243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620580PMC
October 2015

Genome-wide association studies in Africans and African Americans: expanding the framework of the genomics of human traits and disease.

Public Health Genomics 2015 26;18(1):40-51. Epub 2014 Nov 26.

Genomic research is one of the tools for elucidating the pathogenesis of diseases of global health relevance and paving the research dimension to clinical and public health translation. Recent advances in genomic research and technologies have increased our understanding of human diseases, genes associated with these disorders, and the relevant mechanisms. Genome-wide association studies (GWAS) have proliferated since the first studies were published several years ago and have become an important tool in helping researchers comprehend human variation and the role genetic variants play in disease. However, the need to expand the diversity of populations in GWAS has become increasingly apparent as new knowledge is gained about genetic variation. Inclusion of diverse populations in genomic studies is critical to a more complete understanding of human variation and elucidation of the underpinnings of complex diseases. In this review, we summarize the available data on GWAS in recent African ancestry populations within the western hemisphere (i.e. African Americans and peoples of the Caribbean) and continental African populations. Furthermore, we highlight ways in which genomic studies in populations of recent African ancestry have led to advances in the areas of malaria, HIV, prostate cancer, and other diseases. Finally, we discuss the advantages of conducting GWAS in recent African ancestry populations in the context of addressing existing and emerging global health conditions.
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http://dx.doi.org/10.1159/000367962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418477PMC
August 2015
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