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CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease.
Hoh BL, Gong Y, McDonough CW, Waters MF, Royster AJ, Sheehan TO, Burkley B, Langaee TY, Mocco J, Zuckerman SL, Mummareddy N, Stephens ML, Ingram C, Shaffer CM, Denny JC, Brilliant MH, Kitchner TE, Linneman JG, Roden DM, Johnson JA
(2016) J Neurosurg 124: 1746-51
MeSH Terms: Aged, Aspirin, Carboxylic Ester Hydrolases, Clopidogrel, Cytochrome P-450 CYP2C19, Female, Gene Frequency, Genotyping Techniques, Heterozygote, Humans, Intracranial Arteriosclerosis, Ischemic Attack, Transient, Kaplan-Meier Estimate, Male, Myocardial Infarction, Platelet Aggregation Inhibitors, Polymorphism, Single Nucleotide, Prospective Studies, Stroke, Ticlopidine
Show Abstract · Added March 14, 2018
OBJECT Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients. METHODS Genotype testing for CYP2C19*2, (*)3, (*)8, (*)17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months. RESULTS The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03-0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08-0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06-1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05-1.04, p = 0.056). CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations.
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20 MeSH Terms
A novel splice site mutation in SMARCAL1 results in aberrant exon definition in a child with Schimke immunoosseous dysplasia.
Carroll C, Hunley TE, Guo Y, Cortez D
(2015) Am J Med Genet A 167A: 2260-4
MeSH Terms: Arteriosclerosis, Child, DNA Helicases, DNA Replication, Exons, Female, Gene Expression, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Introns, Lymphocytes, Mutation, Nephrotic Syndrome, Osteochondrodysplasias, Pedigree, Pulmonary Embolism, RNA Splice Sites
Show Abstract · Added February 4, 2016
Schimke Immunoosseous Dysplasia (SIOD) is a rare, autosomal recessive disorder of childhood characterized by spondyloepiphyseal dysplasia, focal segmental glomerulosclerosis and renal failure, T-cell immunodeficiency, and cancer in certain instances. Approximately half of patients with SIOD are reported to have biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA translocase that localizes to sites of DNA replication and repairs damaged replication forks. We present a novel mutation (NM_014140.3:c.2070+2insT) that results in defective SMARCAL1 mRNA splicing in a child with SIOD. This mutation, within the donor site of intron 12, results in the skipping of exon 12, which encodes part of a critical hinge region connecting the two lobes of the ATPase domain. This mutation was not recognized as deleterious by diagnostic SMARCAL1 sequencing, but discovered through next generation sequencing and found to result in absent SMARCAL1 expression in patient-derived lymphoblasts. The splicing defect caused by this mutation supports the concept of exon definition. Furthermore, it illustrates the need to broaden the search for SMARCAL1 mutations in patients with SIOD lacking coding sequence variants.
© 2015 Wiley Periodicals, Inc.
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18 MeSH Terms
Routine clinical evaluation of cerebrovascular reserve capacity using carbogen in patients with intracranial stenosis.
Donahue MJ, Dethrage LM, Faraco CC, Jordan LC, Clemmons P, Singer R, Mocco J, Shyr Y, Desai A, O'Duffy A, Riebau D, Hermann L, Connors J, Kirshner H, Strother MK
(2014) Stroke 45: 2335-41
MeSH Terms: Adult, Aged, Brain, Carbon Dioxide, Cerebrovascular Circulation, Constriction, Pathologic, Female, Humans, Intracranial Arteriosclerosis, Male, Middle Aged, Moyamoya Disease, Oxygen
Show Abstract · Added February 19, 2015
BACKGROUND AND PURPOSE - A promising method for identifying hemodynamic impairment that may serve as a biomarker for stroke risk in patients with intracranial stenosis is cerebrovascular reactivity (CVR) mapping using noninvasive MRI. Here, abilities to measure CVR safely in the clinic using hypercarbic hyperoxic (carbogen) gas challenges, which increase oxygen delivery to tissue, are investigated.
METHODS - In sequence with structural and angiographic imaging, blood oxygenation level-dependent carbogen-induced CVR scans were performed in patients with symptomatic intracranial stenosis (n=92) and control (n=10) volunteers, with a subgroup of patients (n=57) undergoing cerebral blood flow-weighted pseudocontinuous arterial spin labeling CVR. Subjects were stratified for 4 substudies to evaluate relationships between (1) carbogen and hypercarbic normoxic CVR in healthy tissue (n=10), (2) carbogen cerebral blood flow CVR and blood oxygenation level-dependent CVR in intracranial stenosis patients (n=57), (3) carbogen CVR and clinical measures of disease in patients with asymmetrical intracranial atherosclerotic (n=31) and moyamoya (n=29) disease, and (4) the CVR scan and immediate and longer-term complications (n=92).
RESULTS - Noninvasive blood oxygenation level-dependent carbogen-induced CVR values correlate with (1) lobar hypercarbic normoxic gas stimuli in healthy tissue (R=0.92; P<0.001), (2) carbogen-induced cerebral blood flow CVR in patients with intracranial stenosis (R=0.30-0.33; P<0.012), and (3) angiographic measures of disease severity both in atherosclerotic and moyamoya patients after appropriate processing. No immediate stroke-related complications were reported in response to carbogen administration; longer-term neurological events fell within the range for expected events in this patient population.
CONCLUSIONS - Carbogen-induced CVR elicited no added adverse events and provided a surrogate marker of cerebrovascular reserve consistent with intracranial vasculopathy.
© 2014 American Heart Association, Inc.
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13 MeSH Terms
Schimke Immunoosseous Dysplasia associated with undifferentiated carcinoma and a novel SMARCAL1 mutation in a child.
Carroll C, Badu-Nkansah A, Hunley T, Baradaran-Heravi A, Cortez D, Frangoul H
(2013) Pediatr Blood Cancer 60: E88-90
MeSH Terms: Amino Acid Substitution, Arteriosclerosis, Carcinoma, Child, Preschool, DNA Helicases, Humans, Immunologic Deficiency Syndromes, Male, Mutation, Missense, Nephrotic Syndrome, Nose Neoplasms, Osteochondrodysplasias, Pulmonary Embolism
Show Abstract · Added February 25, 2014
Schimke Immunoosseous Dysplasia (SIOD) is a rare, autosomal recessive disorder of childhood with classical features of spondyloepiphyseal dysplasia, renal failure, and T cell immunodeficiency. SIOD has been associated with several malignancies, including non-Hodgkin lymphoma and osteosarcoma. About half of SIOD patients have biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1). This gene encodes an annealing helicase and replication stress response protein that localizes to damage-stalled DNA replication forks. We report a child with SIOD and a novel S859P missense mutation in SMARCAL1 who developed undifferentiated carcinoma of the sinus.
Copyright © 2013 Wiley Periodicals, Inc.
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13 MeSH Terms
SMARCAL1 and replication stress: an explanation for SIOD?
Bansbach CE, Boerkoel CF, Cortez D
(2010) Nucleus 1: 245-8
MeSH Terms: Arteriosclerosis, DNA Damage, DNA Helicases, DNA Replication, Gene Silencing, Humans, Immunologic Deficiency Syndromes, Nephrotic Syndrome, Osteochondrodysplasias, Pulmonary Embolism
Show Abstract · Added March 5, 2014
The SNF2 family of ATPases acts in the context of chromatin to regulate transcription, replication, repair and recombination. Defects in SNF2 genes cause many human diseases. For example, mutations in SMARCAL1 (also named HARP) cause Schimke immuno-osseous dysplasia (SIOD); a multi-system disorder characterized by growth defects, immune deficiencies, renal failure and other complex phenotypes. Several groups including ours recently identified SMARCAL1 as a replication stress response protein. Importantly, SMARCAL1 localizes to stalled replication forks and this localization of SMARCAL1 activity prevents DNA damage accumulation during DNA replication. We determined that SIOD-related SMARCAL1 mutants could not prevent replication-associated DNA damage in cells in which endogenous SMARCAL1 was silenced, establishing the first link between SIOD and a defect in a specific biological activity. Here, we also report that cells from patients with SIOD exhibit elevated levels of DNA damage that can be rescued by re-introduction of wild-type SMARCAL1. Our data suggest that loss of SMARCAL1 function in patients may cause DNA replication-associated genome instability that contributes to the pleiotropic phenotypes of SIOD.
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10 MeSH Terms
Natural killer T cells and atherosclerosis: form and function meet pathogenesis.
Braun NA, Covarrubias R, Major AS
(2010) J Innate Immun 2: 316-24
MeSH Terms: Adaptive Immunity, Animals, Arteriosclerosis, Chronic Disease, Cytokines, Dyslipidemias, Glycolipids, Humans, Immunity, Innate, Inflammation, Mice, Natural Killer T-Cells
Show Abstract · Added February 11, 2014
Atherosclerosis is a chronic inflammatory disease characterized by dyslipidemia and accumulation of lipids in the arterial intima, with activation of both innate and adaptive immunity. Reciprocally, dyslipidemia associated with atherosclerosis can perturb normal immune function. Natural killer T (NKT) cells are a specialized group of immune cells that share characteristics with both conventional T cells and natural killer cells. However, unlike these cells, NKT cells recognize glycolipid antigens and produce both pro- and anti-inflammatory cytokines upon activation. Because of these unique characteristics, NKT cells have recently been ascribed a role in the regulation of immunity and inflammation, including cardiovascular disease. In addition, NKT cells represent a bridge between dyslipidemia and immune regulation. This review summarizes the current knowledge of NKT cells and discusses the interplay between dyslipidemia and the normal functions of NKT cells and how this might modulate inflammation and atherosclerosis.
(c) 2010 S. Karger AG, Basel.
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12 MeSH Terms
Association of coronary artery and aortic calcium with lumbar bone density: the MESA Abdominal Aortic Calcium Study.
Hyder JA, Allison MA, Wong N, Papa A, Lang TF, Sirlin C, Gapstur SM, Ouyang P, Carr JJ, Criqui MH
(2009) Am J Epidemiol 169: 186-94
MeSH Terms: Age Factors, Aged, Aged, 80 and over, Aorta, Abdominal, Aortic Diseases, Arteriosclerosis, Bone Density, Calcinosis, Coronary Artery Disease, Coronary Vessels, Female, Humans, Inflammation, Lumbar Vertebrae, Male, Middle Aged, Models, Statistical, Multivariate Analysis, Prevalence, Prospective Studies, Risk Factors, Sex Factors
Show Abstract · Added February 15, 2014
Atherosclerosis and osteoporosis share many risk factors, but their independent association is unclear. The authors investigated the independent associations between volumetric trabecular bone mineral density (vBMD) of the lumbar spine and coronary artery calcium (CAC) and abdominal aortic calcium (AAC). During 2002-2005, they used quantitative computed tomography to assess vBMD and the presence and extent of CAC and AAC among 946 women (mean age = 65.5 years) and 963 men (mean age = 64.1 years) in a substudy of the Multi-Ethnic Study of Atherosclerosis. Prevalences of CAC were 47% and 68% in women and men, respectively, and AAC prevalences were 70% and 73%. Sequential, sex-specific regression models included adjustment for age, ethnicity, body mass index, hypertension, dyslipidemia, diabetes mellitus, smoking, alcohol consumption, physical activity, interleukin-6, C-reactive protein, homocysteine, and sex hormones. After full adjustment, lower vBMD was associated with greater CAC score among women (P < 0.002) and greater AAC score among women (P = 0.004) and men (P < 0.001). After adjustment, vBMD quartile was inversely associated with CAC prevalence (P-trend = 0.05) in women and AAC prevalence (P-trend < 0.01) in men. Partially and fully adjusted models showed similar results. Though modest, these significant, independent associations suggest that atherosclerosis and bone loss may be related.
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22 MeSH Terms
Serum fetuin-a concentration and endothelial dysfunction in chronic kidney disease.
Caglar K, Yilmaz MI, Saglam M, Cakir E, Kilic S, Sonmez A, Eyileten T, Yenicesu M, Oguz Y, Tasar M, Vural A, Ikizler TA, Stenvinkel P, Lindholm B
(2008) Nephron Clin Pract 108: c233-40
MeSH Terms: Adult, Arteriosclerosis, Biomarkers, Blood Proteins, Endothelium, Vascular, Female, Humans, Kidney Failure, Chronic, Male, alpha-2-HS-Glycoprotein
Show Abstract · Added September 29, 2014
BACKGROUND - Defective endothelial function, an initial step in the development of atherosclerotic plaque, is prevalent in moderate to advanced chronic kidney disease (CKD). In this study, the investigators hypothesized that fetuin-A, a calcification inhibitor, is a novel risk factor for the development of endothelial dysfunction in patients.
METHODS - 198 nondiabetic patients with a mean age of 44.0 +/- 12.4 years and with different stages of CKD were studied. In addition to a detailed metabolic panel, flow-mediated dilatation assessed by high-resolution brachial ultrasonography was performed to determine endothelial dysfunction. Carotid intima-media thickness was also estimated by ultrasonography. Serum fetuin-A concentrations were determined by using a human ELISA method.
RESULTS - Endothelial dysfunction was observed in all stages (1-5) of CKD and worsened in parallel to the reduction in estimated glomerular filtration rate. Serum fetuin-A concentrations were also found to be decreased in all but stage 1 CKD. On multiple regression analysis, endothelial dysfunction was independently associated with fetuin-A (beta = 0.745, p < 0.001) and intact parathyroid hormone concentrations (beta = -0.216, p < 0.001).
CONCLUSION - These data in a selected cohort of CKD patients indicate that fetuin-A may be one of the contributing factors for the development of endothelial dysfunction in CKD patients.
Copyright 2008 S. Karger AG, Basel.
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10 MeSH Terms
The relation between visceral fat measurement and torso level--is one level better than another? The Atherosclerosis Risk in Communities Study, 1990-1992.
Warren M, Schreiner PJ, Terry JG
(2006) Am J Epidemiol 163: 352-8
MeSH Terms: Adiposity, Aged, Arteriosclerosis, Body Fat Distribution, Epidemiologic Studies, Female, Humans, Intra-Abdominal Fat, Magnetic Resonance Imaging, Male, Middle Aged, Residence Characteristics, Risk Assessment, Risk Factors, United States
Show Abstract · Added February 24, 2014
Intraabdominal fat (IAF) area is often measured indirectly in epidemiologic studies. The authors recruited 147 participants from the second examination (1990-1992) of the Atherosclerosis Risk in Communities Study to examine IAF area and determine whether there were differences in IAF area and distribution by location. Magnetic resonance imaging was used to image four 10-mm slices between the second and fourth lumbar vertebrae by an inverse recovery method, and IAF was calculated from each image. The authors constructed gender-specific mixed models with IAF area as the outcome and the location of imaging along the torso as the independent variable, using random intercepts to account for between-person variation in IAF area. The torso location of IAF measurement was a significant predictor of IAF area in both men (p = 0.02) and women (p < 0.0001) after adjustment for body mass index. A significant positive interaction between age and location was seen in men, with increasing IAF area moving down the torso with older ages. Using magnetic resonance imaging, location along the torso yields different IAF areas and distributions independently of body mass index in both genders, with measurement at the second lumbar vertebra (slightly above the umbilicus) capturing the largest amount of IAF. Studies that attempt to link IAF with cardiovascular disease risk factors should consider measurement location to accurately capture the association.
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15 MeSH Terms
Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice.
Burleigh ME, Babaev VR, Yancey PG, Major AS, McCaleb JL, Oates JA, Morrow JD, Fazio S, Linton MF
(2005) J Mol Cell Cardiol 39: 443-52
MeSH Terms: Animals, Aorta, Apolipoproteins E, Arteriosclerosis, Cells, Cultured, Chemokine CCL2, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Female, Immunohistochemistry, Indomethacin, Lactones, Lipopolysaccharides, Liver Transplantation, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitrobenzenes, Prostaglandin-Endoperoxide Synthases, Sulfonamides, Sulfones, Transplantation, Heterologous, Tumor Necrosis Factor-alpha
Show Abstract · Added February 11, 2014
Cyclooxygenase (COX) 2 is expressed in atherosclerotic lesions. We have previously reported that selective inhibition of COX-2 reduces early atherosclerosis in LDLR deficient mice. To examine the role of COX-2 in atherosclerosis in other mouse models, we studied the effects of selective COX-2 inhibition (by rofecoxib and NS-398) and nonselective COX inhibition (by indomethacin) on early atherosclerotic lesion formation in apolipoprotein E-deficient (apoE(-/-)) mice. Selective COX-2 and nonselective COX inhibition reduced atherosclerosis in female apoE(-/-) mice by 35-38% and 38-51% in the proximal and en face aortas, respectively. Next we investigated the role of macrophage COX-2 by transplanting COX-2(-/-) fetal liver cells into C57BL/6 mice and challenging the mice with an atherogenic diet. Genetic deletion of COX-2 from hematopoietic cells reduced atherosclerosis by 51%. In addition, LPS activated COX-2(-/-) macrophages had decreased expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNFalpha). The results demonstrate that selective inhibition of COX-2 and elimination of COX-2 from macrophages significantly reduces early atherosclerotic lesion formation in apoE-deficient and C57BL/6 mice. These results are compatible with COX-2 expression by macrophages having a proatherogenic role, and support the potential of anti-inflammatory therapeutic approaches for atherosclerosis.
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26 MeSH Terms