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"Ryan, Kathleen A."
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Analysis of the Gut Microbiota in the Old Order Amish and Its Relation to the Metabolic Syndrome
Obesity has been linked to the human gut microbiota; however, the contribution of gut bacterial species to the obese phenotype remains controversial because of conflicting results from studies in different populations. To explore the possible dysbiosis of gut microbiota in obesity and its metabolic complications, we studied men and women over a range of body mass indices from the Old Order Amish sect, a culturally homogeneous Caucasian population of Central European ancestry. We characterized the gut microbiota in 310 subjects by deep pyrosequencing of bar-coded PCR amplicons from the V1-V3 region of the 16S rRNA gene. Three communities of interacting bacteria were identified in the gut microbiota, analogous to previously identified gut enterotypes. Neither BMI nor any metabolic syndrome trait was associated with a particular gut community. Network analysis identified twenty-two bacterial species and four OTUs that were either positively or inversely correlated with metabolic syndrome traits, suggesting that certain members of the gut microbiota may play a role in these metabolic derangements.
Journal Article
Effects of the BDNF Val66Met polymorphism on functional status and disability in young stroke patients
The preponderance of evidence from recent studies in human subjects supports a negative effect of the BDNF Val66Met polymorphism on motor outcomes and motor recovery. However prior studies have generally reported the effect of the Met allele in older stroke patients, while potential effects in younger stroke patients have remained essentially unexamined. The lack of research in younger patients is significant since aging effects on CNS repair and functional recovery after stroke are known to interact with the effects of genetic polymorphisms. Here we present a study of first-ever ischemic stroke patients aged 15-49 years that examines the effect of Met carrier status on functional disability.
829 patients with a first ischemic stroke (Average age = 41.4 years, SD = 6.9) were recruited from the Baltimore-Washington region. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Our sample contained 165 Met carriers and 664 non-Met carriers. Modified Rankin scores as recorded at discharge were obtained from the hospital records by study personnel blinded to genotype, and binarized into \"Good\" versus \"Poor\" outcomes (mRS 0-2 vs. 3+), with mRS scores 3+ reflecting a degree of disability that causes loss of independence.
Our analysis showed that the Met allele conveyed a proportionally greater risk for poor outcomes and disability-related loss of independence with mRS scores 3+ (adjusted OR 1.73, 95% CI 1.13-2.64, p = 0.01).
The BDNF Val66Met polymorphism was negatively associated with functional outcomes at discharge in our sample of 829 young stroke patients. This finding stands in contrast to what would be predicted under the tenets of the resource modulation hypothesis (i.e. that younger patients would be spared from the negative effect of the Met allele on recovery since it is posited to arise as a manifestation of age-related decline in physiologic resources).
Journal Article
Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program
Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7–12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.
Journal Article
Randomized evaluation of the loss‐of‐function carboxylesterase 1 (CES1) G143E variant on clopidogrel and ticagrelor pharmacodynamics
Antiplatelet therapy with a P2Y12 receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss‐of‐function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on‐clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by CES1 G143E genotype (N = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate‐stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E‐allele carriers vs. non‐carriers, respectively, p = 3.8 × 10−5). Similar significant effects on platelet aggregation were also noted between 143E‐allele carriers versus non‐carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, p = 0.04), epinephrine (44.4 vs. 18.8%, p = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, p = 3.7 × 10−3). In contrast, no relationship between CES1 G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on‐clopidogrel platelet aggregation is substantially modified by CES1 G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response‐modifying alleles in CES1.
Journal Article
Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction
Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.
Journal Article
Evaluation of WISP1 as a candidate gene for bone mineral density in the Old Order Amish
Wnt1-inducible signaling pathway protein-1 (
WISP1
) is a novel target of the Wnt pathway for modulating osteogenesis and improving bone strength. However, it is not clear if genetic variants in the
WISP1
region are associated with bone mineral density (BMD) in human. The aim of this study is to investigate the role of genetic variation in
WISP1
gene as a determinant of BMD in 1,510 Old Order Amish (OOA). We performed regional association analysis of 58 tag variants within 5 kb upstream and downstream to
WISP1
with BMD and found 5 variants that were associated with BMD at multiple skeletal sites (
P
values from 2.89 × 10
−6
to 1.62 × 10
−2
), with some significant associations even after adjustment for multiple comparisons. To replicate these results in an independent dataset, we performed a look-up of BMD associations with these variants in European ancestry subjects from the large GEFOS Consortium and observed the nominal associations of two of these variants with BMD (
P
values: 0.031 to 0.048). In conclusion, we have demonstrated that genetic variants surrounding
WISP1
are associated with BMD at multiple skeletal sites in the OOA, thus influencing osteoporosis risk. These results support a role for the
WISP1
gene on influencing variation in BMD.
Journal Article
Correlation of Circulating MMP-9 with White Blood Cell Count in Humans: Effect of Smoking
Matrix metalloproteinase-9 (MMP-9) is an emerging biomarker for several disease conditions, where white blood cell (WBC) count is also elevated. In this study, we examined the relationship between MMP-9 and WBC levels in apparently healthy smoking and non-smoking human subjects.
We conducted a cross-sectional study to assess the relationship of serum MMP-9 with WBC in 383 men and 356 women. Next, we divided the male population (women do not smoke in this population) into three groups: never (n = 243), current (n = 76) and former (n = 64) smokers and compared the group differences in MMP-9 and WBC levels and their correlations within each group.
Circulating MMP-9 and WBC count are significantly correlated in men (R(2) = 0.13, p<0.001) and women (R(2) = 0.19, p<0.001). After stratification by smoking status, MMP-9 level was significantly higher in current smokers (mean ± SE; 663.3±43.4 ng/ml), compared to never (529.7±20.6) and former smokers (568±39.3). WBC count was changed in a similar pattern. Meanwhile, the relationship became stronger in current smokers with increased correlation coefficient of r = 0.45 or R(2) = 0.21 (p<0.001) and steeper slope of ß = 1.16±0.30 (p<0.001) in current smokers, compared to r = 0.26 or R(2) = 0.07 (p<0.001) and ß = 0.34±0.10 (p<0.001) in never smokers.
WBC count accounts for 13% and 19% of MMP-9 variance in men and women, respectively. In non-smoking men, WBC count accounts for 7% of MMP-9 variance, but in smoking subjects, it accounts for up to 21% of MMP-9 variance. Thus, we have discovered a previously unrecognized correlation between the circulating MMP-9 and WBC levels in humans.
Journal Article
School-Located Influenza Vaccination Reduces Community Risk for Influenza and Influenza-Like Illness Emergency Care Visits
School-located influenza vaccination (SLIV) programs can substantially enhance the sub-optimal coverage achieved under existing delivery strategies. Randomized SLIV trials have shown these programs reduce laboratory-confirmed influenza among both vaccinated and unvaccinated children. This work explores the effectiveness of a SLIV program in reducing the community risk of influenza and influenza-like illness (ILI) associated emergency care visits.
For the 2011/12 and 2012/13 influenza seasons, we estimated age-group specific attack rates (AR) for ILI from routine surveillance and census data. Age-group specific SLIV program effectiveness was estimated as one minus the AR ratio for Alachua County versus two comparison regions: the 12 county region surrounding Alachua County, and all non-Alachua counties in Florida.
Vaccination of ∼50% of 5-17 year-olds in Alachua reduced their risk of ILI-associated visits, compared to the rest of Florida, by 79% (95% confidence interval: 70, 85) in 2011/12 and 71% (63, 77) in 2012/13. The greatest indirect effectiveness was observed among 0-4 year-olds, reducing AR by 89% (84, 93) in 2011/12 and 84% (79, 88) in 2012/13. Among all non-school age residents, the estimated indirect effectiveness was 60% (54, 65) and 36% (31, 41) for 2011/12 and 2012/13. The overall effectiveness among all age-groups was 65% (61, 70) and 46% (42, 50) for 2011/12 and 2012/13.
Wider implementation of SLIV programs can significantly reduce the influenza-associated public health burden in communities.
Journal Article