Baltimore Geriatric Research

Baltimore, MD, United States

Baltimore Geriatric Research

Baltimore, MD, United States

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Bellenguez C.,University of Oxford | Bevan S.,St George's, University of London | Gschwendtner A.,Ludwig Maximilians University of Munich | Spencer C.C.A.,University of Oxford | And 99 more authors.
Nature Genetics | Year: 2012

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes. © 2012 Nature America, Inc. All rights reserved.


Prokopenko I.,University of Oxford | Prokopenko I.,Imperial College London | Poon W.,Lund University | Magi R.,University of Oxford | And 83 more authors.
PLoS Genetics | Year: 2014

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father. © 2014.


Malik R.,Ludwig Maximilians University of Munich | Bevan S.,St George's, University of London | Nalls M.A.,U.S. National Institute on Aging | Holliday E.G.,University of Newcastle | And 33 more authors.
Stroke | Year: 2014

Background and Purpose - Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts. Methods - Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS. Results - A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification. Conclusions - A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small. © 2014 American Heart Association, Inc.


Capuano M.M.,University of Maryland Baltimore County | Sorkin J.D.,University of Maryland Baltimore County | Sorkin J.D.,Veterans Affairs Medical Center | Sorkin J.D.,Baltimore Geriatric Research | And 7 more authors.
BMC Research Notes | Year: 2013

Background: SOCS7 is a member of the suppressor of cytokine signaling family of proteins and is expressed in skeletal muscle and islets. SOCS7 deficient mice develop islet hyperplasia in the setting of increased insulin sensitivity and normal glucose tolerance. The objective of this study was to determine if variants in SOCS7 play a role in variation of glucose and insulin levels and the development of type 2 diabetes (T2DM). Results: Five SOCS7 tagging SNPs were genotyped in diabetic and nondiabetic Old Order Amish. A case-control study was performed in T2DM (n = 145) and normal glucose tolerant (n = 358) subjects. Nominal associations were observed with T2DM and the minor alleles for rs8068600 (P = 0.01) and rs8074124 (P = 0.04); however, only rs8068600 remained significant after Bonferroni adjustment for multiple comparisons (P = 0.01). Among nondiabetic Amish (n = 765), no significant associations with glucose or insulin traits including fasting or 2 hour glucose and insulin from the oral glucose tolerance test, insulin or glucose area under the curve, Matsuda Index or HOMA-IR were found for any of the SNPs. Conclusion: In conclusion, genetic variants in the SOCS7 gene do not impact variation in glucose homeostasis traits and only minimally impact risk of T2DM in the Old Order Amish. Our study was not able to address whether rare variants that potentially impact gene function might influence T2DM risk. © 2013 Capuano et al.; licensee BioMed Central Ltd.


Serra M.C.,University of Maryland Baltimore County | Serra M.C.,Baltimore Geriatric Research | Ryan A.S.,University of Maryland Baltimore County | Ryan A.S.,Baltimore Geriatric Research | And 6 more authors.
Obesity | Year: 2015

Objective To determine whether higher subcutaneous adipose tissue lipoprotein lipase activity (AT-LPLA) is associated with greater triglyceride (TG) storage in subcutaneous adipose tissue (SAT), thereby reducing visceral adipose tissue (VAT) accumulation and metabolic dysfunction. Methods Obese postmenopausal women (60 ± 1 years, mean ± SEM; N = 101) had body composition measured by DXA and CT and had fat aspirations to measure fat cell weight (FCW) and AT-LPLA. Women were ranked by visceral to total abdominal fat ratio (VAT/TAF), and the lowest and highest groups (n = 24) matched for % fat and age. Results The prevalence of metabolic dysfunction was 7-to 10-fold higher in women with high VAT/TAF (Ps < 0.01). Women with low VAT/TAF had 11% and 6% lower abdominal and gluteal FCW but 28% and 54% higher AT-LPLA/106 cells in abdominal and gluteal fat, respectively. Abdominal FCW correlated with AT-LPLA in women with low (r = 0.63, P < 0.01) but not high (r = 0.14, P = 0.52) VAT/TAF, and these lines differed in slope (P < 0.05) and intercept (P < 0.01), suggesting greater capacity for TG storage with low VAT/TAF. There were no relationships between gluteal FCW and AT-LPLA. The relationship between SAT and abdominal AT-LPLA (r = 0.39, P < 0.01) suggests that higher AT-LPLA promotes TG storage. Conclusions These results suggest that higher AT-LPLA is associated with SAT adipocyte hypertrophy, which reduces visceral adiposity and metabolic risk in obese, older women. © 2015 The Obesity Society.


Ryan A.S.,University of Maryland Baltimore County | Ryan A.S.,Baltimore Geriatric Research | Li G.,University of Maryland Baltimore County | Li G.,Baltimore Geriatric Research | And 4 more authors.
Obesity | Year: 2013

Objective To determine whether aerobic exercise training + weight loss (AEX + WL) would affect the expression of myostatin and its relationship with insulin sensitivity in a longitudinal, clinical intervention study. Design and Methods Thirty-three obese sedentary postmenopausal women and men (n = 17 and 16, age: 61 ± 1 years, body mass index: 31 ± 1 kg/m2, VO2max: 21.9 ± 1.0 mL/kg/min, X ± Standard error of the mean (SEM)) completed 6 months of 3 days/week AEX + WL. During an 80 mU m -2 min-1 hyperinsulinemic-euglycemic clamp, we measured glucose utilization (M), myostatin, myogenin, and MyoD gene expression by real-time RT-PCR in vastus lateralis muscle at baseline and 2 h. Results Body weight (-8%) and fat mass (-17%) decreased after AEX + WL (P < 0.001). Fat-free mass (FFM) and mid-thigh muscle area by computed tomography did not change but muscle attenuation increased (P < 0.05). VO2max increased 14% (P < 0.001). AEX + WL increased M by 18% (P < 0.01). Myostatin gene expression decreased 19% after AEX + WL (P < 0.05). Basal mRNA myostatin levels were negatively associated with M before the intervention (r = -0.43, P < 0.05). Insulin infusion increased myoD and myogenin expression before and after AEX + WL (both P < 0.001) but basal levels did not change. The insulin effect on myostatin expression was associated with the change in M after AEX + WL (r = 0.56, P < 0.005). Conclusions Exercise and weight loss results in a downregulation of myostatin mRNA and an improvement in insulin sensitivity in obese older men and women. Copyright © 2012 The Obesity Society.

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