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Search Results: 1 - 10 of 87654 matches for " Donald W Bowden "
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Genetic analysis of haptoglobin polymorphisms with cardiovascular disease and type 2 diabetes in the diabetes heart study
Jeremy N Adams, Amanda J Cox, Barry I Freedman, Carl D Langefeld, J Jeffrey Carr, Donald W Bowden
Cardiovascular Diabetology , 2013, DOI: 10.1186/1475-2840-12-31
Abstract: This study examined the association of HP genotypes with subclinical CVD, T2DM risk, and associated risk factors in a T2DM-enriched sample. Haptoglobin genotypes were determined in 1208 European Americans (EA) from 473 Diabetes Heart Study (DHS) families via PCR. Three promoter SNPs (rs5467, rs5470, and rs5471) were also genotyped.Analyses revealed association between HP2-2 duplication and increased carotid intima-media thickness (IMT; p?=?0.001). No association between HP and measures of calcified arterial plaque were observed, but the HP polymorphism was associated with triglyceride concentrations (p?=?0.005) and CVD mortality (p?=?0.04). We found that the HP2-2 genotype was associated with increased T2DM risk with an odds ratio (OR) of 1.49 (95% CI 1.18-1.86, p?=?6.59x10-4). Promoter SNPs were not associated with any traits.This study suggests association between the HP duplication and IMT, triglycerides, CVD mortality, and T2DM in an EA population enriched for T2DM. Lack of association with atherosclerotic calcified plaque likely reflect differences in the pathogenesis of these CVD phenotypes. HP variation may contribute to the heritable risk for CVD complications in T2DM.Cardiovascular disease (CVD) is one of the major complications associated with type 2 diabetes mellitus (T2DM). As of 2011, 25.8 million Americans had diagnosed T2DM [1]. More than 50% of individuals with T2DM had coronary heart disease, stroke, or cardiac disease [2]. T2DM is an independent risk factor for development of CVD with the relative risk of CVD mortality of 2.1 in men and 4.9 in women, relative to non-T2DM affected individuals [3,4]. There is increasing evidence that genetic and environmental factors contribute to this risk.Haptoglobin (HP) is a 54 kDa protein, found abundantly in the serum [5,6]. The HP gene has two major alleles: HP1, (containing five exons) and HP2, (containing seven exons) which likely arose from a duplication event involving exons 3 and 4, producing a 61 kDa pro
Genetic analysis of the GLUT10 glucose transporter (SLC2A10) polymorphisms in Caucasian American type 2 diabetes
Jennifer L Bento, Donald W Bowden, Josyf C Mychaleckyj, Shohei Hirakawa, Stephen S Rich, Barry I Freedman, Fernando Segade
BMC Medical Genetics , 2005, DOI: 10.1186/1471-2350-6-42
Abstract: Twenty SNPs including 4 coding, 10 intronic and 6 5' and 3' to the coding sequence were genotyped across a 100 kb region containing the SLC2A10 gene in DNAs from 300 T2DM cases and 310 controls using the Sequenom MassArray Genotyping System. Allelic association was evaluated, and linkage disequilibrium (LD) and haplotype structure of SLC2A10 were also determined to assess whether any specific haplotypes were associated with T2DM.Of these variants, fifteen had heterozygosities greater than 0.80 and were analyzed further for association with T2DM. No evidence of significant association was observed for any variant with T2DM (all P ≥ 0.05), including Ala206Thr (rs2235491) which was previously reported to be associated with fasting insulin. Linkage disequilibrium analysis suggests that the SLC2A10 gene is contained in a single haplotype block of 14 kb. Haplotype association analysis with T2DM did not reveal any significant differences between haplotype frequencies in T2DM cases and controls.From our findings, we can conclude that sequence variants in or near GLUT10 are unlikely to contribute significantly to T2DM in Caucasian Americans.Multiple genetic studies have been carried out that link human chromosome 20q13.1-13.2 to type 2 diabetes (T2DM) [1-5]. This linkage evidence has led investigators to search for T2DM susceptibility genes in this genomic region. Our laboratory has carried out analysis of specific genes [6-8] and developed high resolution physical maps of the region [9-11]. In an association analysis of genetic markers Price et al. [12] identified three regions of T2DM susceptibility. Among the genes mapped to the linkage disequilibrium regions, a novel facilitative glucose transporter (GLUT) was identified and designated GLUT10 (gene symbol SLC2A10) [6,13]. The gene spans 28 kb of genomic sequence, is split into 5 exons and 4 introns [6,13] and is expressed mainly in heart, liver, lung, skeletal muscle, pancreas, placenta, thyroid, and adipose tissue [6,13
Buffy coat specimens remain viable as a DNA source for highly multiplexed genome-wide genetic tests after long term storage
Josyf C Mychaleckyj, Emily A Farber, Jessica Chmielewski, Jamie Artale, Laney S Light, Donald W Bowden, Xuanlin Hou, Santica M Marcovina
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-91
Abstract: We isolated DNA from 120 Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial buffy coats sampling a range of storage times up to 9 years and other factors that could influence DNA yield. We performed TaqMan SNP and GWA genotyping to test whether the DNA retained integrity for high quality genetic analysis.We tested two QIAGEN automated protocols for DNA isolation, preferring the Compromised Blood Protocol despite similar yields. We isolated DNA from all 120 specimens (yield range 1.1-312 ug per 8.5 ml ACD tube of whole blood) with only 3/120 samples yielding < 10 ug DNA. Age of participant at blood draw was negatively associated with yield (mean change -2.1 ug/year). DNA quality was very good based on gel electrophoresis QC, TaqMan genotyping of 6 SNPs (genotyping no-call rate 1.1% in 702 genotypes), and excellent quality GWA genotyping data (maximum per sample genotype missing rate 0.64%).When collected as a long term clinical trial or biobank specimen for DNA, buffy coats can be stored for up to 9 years in a -80degC frozen state and still produce high yields of DNA suitable for GWA analysis and other genetic testing.The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is registered with ClinicalTrials.gov, number NCT00000620.Clinical trials and prospective observational cohort studies are complex to design and costly to implement, hence there is a strong desire to maximize overall clinical and scientific return on investment. A common strategy is to include blood specimen collection at a baseline or early participant study visit to enable future ancillary studies or analysis of secondary biomarker outcomes. The blood specimens may be processed to produce aliquots of sera, plasma, or blood cell pack that are stored frozen for future use. For genetics studies, DNA is more stable under long-term freezer storage, but in many existing or completed studies, the study protocol required the extraction and storage of buffy coats (aliqu
Evaluation of Candidate Nephropathy Susceptibility Genes in a Genome-Wide Association Study of African American Diabetic Kidney Disease
Nicholette D. Palmer, Maggie C. Y. Ng, Pamela J. Hicks, Poorva Mudgal, Carl D. Langefeld, Barry I. Freedman, Donald W. Bowden
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088273
Abstract: Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a complex disorder resulting from the combined influence of genetic and environmental factors. This study contains a comprehensive genetic analysis of putative nephropathy loci in 965 African American (AA) cases with T2D-ESKD and 1029 AA population-based controls extending prior findings. Analysis was based on 4,341 directly genotyped and imputed single nucleotide polymorphisms (SNPs) in 22 nephropathy candidate genes. After admixture adjustment and correction for multiple comparisons, 37 SNPs across eight loci were significantly associated (1.6E-05
Human Lipoxygenase Pathway Gene Variation and Association with Markers of Subclinical Atherosclerosis in the Diabetes Heart Study
Kathryn P. Burdon,Megan E. Rudock,Allison B. Lehtinen,Carl D. Langefeld,Donald W. Bowden,Thomas C. Register,Yongmei Liu,Barry I. Freedman,J. Jeffrey Carr,Catherine C. Hedrick,Stephen S. Rich
Mediators of Inflammation , 2010, DOI: 10.1155/2010/170153
Abstract: Aims. Genes of the 5-lipoxygenase pathway are compelling candidates for atherosclerosis. We hypothesize that polymorphisms in ALOX12, ALOX15, ALOX5, and ALOX5AP genes are associated with subclinical atherosclerosis in multiple vascular beds. Methods. Families with two or more siblings with type 2 diabetes and their nondiabetic siblings were studied as part of the Diabetes Heart Study (DHS). European American diabetic ( ) and nondiabetic ( ) siblings were genotyped for SNPs in the ALOX12, ALOX15, ALOX5, and ALOX5AP genes. Subclinical measures of atherosclerosis (IMT, coronary (CorCP), carotid (CarCP) and aortic (AorCP) calcified plaque) were obtained. Results. Associations were observed between ALOX12 with CorCP, ALOX5 with CorCP, AorCP, and IMT, and ALOX5AP with CorCP and CarCP, independent of known epidemiologic risk factors. Further, lipoxygenase pathway SNPs that were associated with measures of atherosclerosis were associated with markers of inflammation (CRP, ICAM-1) and calcification (MGP). Conclusions. Polymorphisms within ALOX12, ALOX5, and ALOX5AP are genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease. 1. Introduction Atherosclerosis is thought to be the result of chronic inflammation of the artery wall although the pathways and factors that initiate and modulate the inflammatory response in atherosclerosis have yet to be completely resolved [1]. Metabolites of arachidonic acid are strong candidates that are recognized for their inflammatory properties. The mouse 5-LO gene, ALOX5, has been shown to contribute to the development of atherosclerosis [2]. Variants in the human homologue (ALOX5) are associated with carotid artery intima-media thickness (IMT) [3]. FLAP (5-lipoxygenase activating protein), encoded by the ALOX5AP gene, likely acts as an arachidonic acid-binding and transfer protein to facilitate 5LO activity [4]. Single SNPs and haplotypes of ALOX5AP have been associated with myocardial infarction in multiple populations [5–7]. Human 12-lipoxygenase (encoded by ALOX12) and 15-lipoxygenase (encoded by ALOX15) have been localized to atherosclerotic plaques, suggesting that 12/15LO activity is involved in the development of atherosclerosis [8–10]. Overexpression of human 15-LO in mouse vascular endothelial cells increased markers of atherosclerosis [11]. Human aortic endothelial cells cultured in chronically
Chromosome 7p linkage and association study for diabetes related traits and type 2 diabetes in an African-American population enriched for nephropathy
Tennille S Leak, Carl D Langefeld, Keith L Keene, Carla J Gallagher, Lingyi Lu, Josyf C Mychaleckyj, Stephen S Rich, Barry I Freedman, Donald W Bowden, Michèle M Sale
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-22
Abstract: We fine mapped this region by genotyping 11 additional polymorphic markers in the same ASP and investigated a total of 68 single nucleotide polymorphisms (SNPs) in functional candidate genes (GCK1, IL6, IGFBP1 and IGFBP3) for association with age of T2D diagnosis, age of ESRD diagnosis, duration of T2D to onset of ESRD, body mass index (BMI) in African American cases and T2D-ESRD in an African American case-control cohort. OSA of fine mapping markers supported linkage at 28 cM on 7p (near D7S3051) in early-onset T2D families (max. LOD = 3.61, P = 0.002). SNPs in candidate genes and 70 ancestry-informative markers (AIMs) were evaluated in 577 African American T2D-ESRD cases and 596 African American controls.The most significant association was observed between ESRD age of diagnosis and SNP rs730497, located in intron 1 of the GCK1 gene (recessive T2D age-adjusted P = 0.0006). Nominal associations were observed with GCK1 SNPs and T2D age of diagnosis (BMI-adjusted P = 0.014 to 0.032). Also, one IGFBP1 and four IGFBP3 SNPs showed nominal genotypic association with T2D-ESRD (P = 0.002-0.049). After correcting for multiple tests, only rs730497 remanined significant.Variant rs730947 in the GCK1 gene appears to play a role in early ESRD onset in African Americans.A genome wide linkage scan was performed on 638 African American affected sibling pairs (ASPs) with type 2 diabetes (T2D) from 247 families; 166 families contained at least one ASP concordant for diabetic end-stage renal disease (T2D-ESRD) [1]. Ordered subset analysis (OSA) revealed a linkage peak on chromosome 7p in the subset of T2D families with an early age of diagnosis (29% of pedigrees, max. LOD = 3.85, P = 0.003 for the change in LOD score) [1]. T2D-ESRD subsets with lower body mass index (BMI) (64% of pedigrees, max. LOD = 3.93, P = 0.010) and longer duration from T2D diagnosis to ESRD onset (37% of pedigrees, max. LOD = 3.59, P = 0.010) also showed evidence for linkage at this locus [2].Fine mapping of th
Extremely Flat Haloes and the Shape of the Galaxy
N. W. Evans,A. Bowden
Physics , 2014, DOI: 10.1093/mnras/stu1113
Abstract: We present a set of highly flattened galaxy models with asymptotically constant rotation curves. The mass density in the equatorial plane falls like (distance)$^{-1}$ at large radii. Although the inner equidensity contours may be spherical, oblate or prolate, the outer parts are always severely flattened. The elongated shape is supported by rotation or tangential velocity anisotropy. The models are thickened Mestel discs, and form a previously undiscovered part of the Miyamoto & Nagai sequence of flattened galaxies. The properties of the models -- axis ratios, velocity dispersions, streaming velocities and distribution functions -- are all discussed in some detail. We pose the question: are extremely flattened or disk-like haloes possible for the Milky Way galaxy? This has never been examined before, as very flattened halo models were not available. We fit the rotation curve and the vertical kinematics of disc stars in the solar neighbourhood to constrain the overall shape of the Galaxy. Denoting the ratio of polar axis to major axis by $q$, we show that models with $q\lesssim 0.57$ cannot simultaneously reproduce the in-plane and out-of-plane constraints. The kinematics of the Sagittarius galaxy also strongly disfavour models with high flattening, as the orbital plane precession is too great and the height reached above the Galactic plane is too small. At least for our Galaxy, the dark halo cannot be flatter than E4 (or axis ratio $q \sim 0.57$) at the Solar circle. Models in which the dark matter is accounted for by a massive baryonic disc or by decaying neutrinos are therefore ruled out by constraints from the rotation curve and the vertical kinematics.
Differential Effects of MYH9 and APOL1 Risk Variants on FRMD3 Association with Diabetic ESRD in African Americans
Barry I. Freedman equal contributor ,Carl D. Langefeld equal contributor ,Lingyi Lu,Jasmin Divers,Mary E. Comeau,Jeffrey B. Kopp,Cheryl A. Winkler,George W. Nelson,Randall C. Johnson,Nicholette D. Palmer,Pamela J. Hicks,Meredith A. Bostrom,Jessica N. Cooke,Caitrin W. McDonough,Donald W. Bowden
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002150
Abstract: Single nucleotide polymorphisms (SNPs) in MYH9 and APOL1 on chromosome 22 (c22) are powerfully associated with non-diabetic end-stage renal disease (ESRD) in African Americans (AAs). Many AAs diagnosed with type 2 diabetic nephropathy (T2DN) have non-diabetic kidney disease, potentially masking detection of DN genes. Therefore, genome-wide association analyses were performed using the Affymetrix SNP Array 6.0 in 966 AA with T2DN and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for c22 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9—a finding replicated in 640 additional AA T2DN cases and 683 NDNN controls. Contrasting all 1,592 T2DN cases with all 1,671 NDNN controls, FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (e.g., rs942280 interaction p-value = 9.3E?7 additive; odds ratio [OR] 0.67). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes (rs942280 OR = 1.28), not in MYH9 E1 risk allele homozygotes (rs942280 OR = 0.80; homogeneity p-value = 4.3E?4). Effects were weaker stratifying on APOL1. FRMD3 SNPS were associated with T2DN, not type 2 diabetes per se, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes.
Dipping Our Toes in the Water: First Models of GD-1 as a Stream
A. Bowden,V. Belokurov,N. W. Evans
Physics , 2015, DOI: 10.1093/mnras/stv285
Abstract: We present a model for producing tidal streams from disrupting progenitors in arbitrary potentials, utilizing the idea that the majority of stars escape from the progenitor's two Lagrange points. The method involves releasing test particles at the Lagrange points as the satellite orbits the host and dynamically evolving them in the potential of both host and progenitor. The method is sufficiently fast to allow large-dimensional parameter exploration using Monte Carlo methods. We provide the first direct modelling of 6-D stream observations -- assuming a stream rather than an orbit -- by applying our methods to GD-1. This is a kinematically cold stream spanning $60^{\circ}$ of the sky and residing in the outer Galaxy $\approx 15$ kpc distant from the centre. We assume the stream moves in a flattened logarithmic potential characterised by an asymptotic circular velocity $v_0$ and a flattening $q$. We recover values of normalisation $v_0$ = $227.2^{+15.6}_{-18.2}$ kms$^{-1}$ and flattening $q$ = $0.91^{+0.04}_{-0.1}$, if the stream is assumed to leading, and $v_0$ = $226.5^{+17.9}_{-17.0}$ kms$^{-1}$, $q$ = $0.90^{+0.05}_{-0.09}$, if it is assumed to be trailing. This can be compared to the values $v_0 = 224 \pm 13$ kms$^{-1}$ and $q= 0.87^{+0.07}_{-0.04}$ obtained by Koposov et al (2010) using the simpler technique of orbit fitting. Although there are differences between stream and orbit fitting, we conclude that orbit fitting can provide accurate results given the current quality of the data, at least for this kinematically cold stream in this logarithmic model of the Galaxy.
On Asymmetric Distributions of Satellite Galaxies
A. Bowden,N. W. Evans,V. Belokurov
Physics , 2014, DOI: 10.1088/2041-8205/793/2/L42
Abstract: We demonstrate that the asymmetric distribution of M31 satellites cannot be produced by tides from the Milky Way as such effects are too weak. However, loosely bound associations and groups of satellites can fall into larger haloes and give rise to asymmetries. We compute the survival times for such associations. We prove that the survival time is always shortest in Keplerian potentials, and can be ~ 3 times longer in logarithmic potentials. We provide an analytical formula for the dispersal time in terms of the size and velocity dispersion of the infalling structure. We show that, if an association of ~10 dwarfs fell into the M31 halo, its present aspect would be that of an asymmetric disk of satellites. We also discuss the case of cold substructure in the Andromeda II and Ursa Minor dwarfs.
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