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1.  Gene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes 
Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development.
PMCID: PMC3939004  PMID: 24596594
Type 2 diabetes; statins; thiazide diuretics; whole blood; gene expression; microarray; supervised normalization; surrogate variable analysis; chemokine ligand 14; zinc finger proteins
2.  Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans: The Candidate Gene Association Resource (CARe) Study 
Background
Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study.
Methods and Results
Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43 × 10−07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 × 10−07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 × 10−08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 × 10−07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN.
Conclusions
In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
doi:10.1161/CIRCGENETICS.111.962365
PMCID: PMC3591479  PMID: 23275298
echocardiography; ethnic; genome-wide association studies; Left atrium genetics; left ventricular mass genetics
3.  Association of Body Mass Index, Diabetes, Hypertension, and Blood Pressure Levels with Risk of Permanent Atrial Fibrillation 
ABSTRACT
BACKGROUND
After an initial episode of atrial fibrillation (AF), AF may recur and become permanent. AF progression is associated with higher morbidity and mortality. Understanding the risk factors for permanent AF could help identify people who would benefit most from interventions.
OBJECTIVE
To determine whether body mass index (BMI), diabetes, hypertension, and blood pressure levels are associated with permanent AF among people whose initial AF episode terminated.
DESIGN
Population-based inception cohort study.
PARTICIPANTS
Enrollees in Group Health, an integrated health care system, aged 30–84 with newly diagnosed AF in 2001–2004, whose initial AF terminated within 6 months and who had at least 6 months of subsequent follow-up (N = 1,385).
MAIN MEASURES
Clinical characteristics were determined from medical records. Permanent AF was determined from medical records and ECG and administrative databases. Permanent AF was defined as AF present on two separate occasions 6–36 months apart, without any documented sinus rhythm between the two occasions. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs).
KEY RESULTS
Five-year cumulative incidence of permanent AF was 24 %. Compared with normal BMI (18.5–24.9 kg/m2), BMI levels of 25.0–29.9 (overweight), 30.0–34.9 (obese 1), 35.0–39.9 (obese 2), and ≥ 40.0 kg/m2 (obese 3) were associated with HRs of permanent AF of 1.26 (95 % CI: 0.92, 1.72); 1.35 (0.96, 1.91); 1.50 (0.97, 2.33); and 1.79 (1.13, 2.84), adjusted for age, sex, diabetes, hypertension, blood pressure, coronary heart disease, valvular heart disease, heart failure, and prior stroke. Diabetes, hypertension, and blood pressure were not associated with permanent AF.
CONCLUSIONS
For people whose initial AF episode terminates, benefits of having lower BMI may include a lower risk of permanent AF. Risk of permanent AF was similar for people with and without diabetes or hypertension and across blood pressure levels.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2220-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-012-2220-4
PMCID: PMC3614136  PMID: 22972153
cohort study; anthropometry; electrocardiogram; atrial fibrillation
5.  Dye-Binding Assays for Evaluation of the Effects of Small Molecule Inhibitors on Amyloid (Aβ) Self-Assembly 
ACS Chemical Neuroscience  2012;3(11):807-819.
Dye-binding assays, such as those utilizing Congo red and thioflavin T, are among the most widely used tools to probe the aggregation of amyloidogenic biomolecules and for the evaluation of small molecule inhibitors of amyloid aggregation and fibrillization. A number of recent reports have indicated that these dye-binding assays could be prone to false positive effects when assessing inhibitors’ potential toward Aβ peptides, species involved in Alzheimer’s disease. Specifically, this review focuses on the application of thioflavin T for determining the efficiency of small molecule inhibitors of Aβ aggregation and addresses potential reasons that might be associated with the false positive effects in an effort to increase reliability of dye-binding assays.
doi:10.1021/cn300076x
PMCID: PMC3503347  PMID: 23173064
Alzheimer’s disease; amyloid peptide; small molecule inhibitor; dye-binding assay; thioflavin T; fluorescence
6.  Asymmetry in infants' selective attention to facial features during visual processing of infant-directed speech 
Two experiments used eye tracking to examine how infant and adult observers distribute their eye gaze on videos of a mother producing infant- and adult-directed speech. Both groups showed greater attention to the eyes than to the nose and mouth, as well as an asymmetrical focus on the talker's right eye for infant-directed speech stimuli. Observers continued to look more at the talker's apparent right eye when the video stimuli were mirror flipped, suggesting that the asymmetry reflects a perceptual processing bias rather than a stimulus artifact, which may be related to cerebral lateralization of emotion processing.
doi:10.3389/fpsyg.2013.00601
PMCID: PMC3769626  PMID: 24062705
infant-directed speech; eye-tracking; face perception; emotion; lateralization; language; speech perception
7.  A systematic review of the evidence for single stage and two stage revision of infected knee replacement 
Background
Periprosthetic infection about the knee is a devastating complication that may affect between 1% and 5% of knee replacement. With over 79 000 knee replacements being implanted each year in the UK, periprosthetic infection (PJI) is set to become an important burden of disease and cost to the healthcare economy. One of the important controversies in treatment of PJI is whether a single stage revision operation is superior to a two-stage procedure. This study sought to systematically evaluate the published evidence to determine which technique had lowest reinfection rates.
Methods
A systematic review of the literature was undertaken using the MEDLINE and EMBASE databases with the aim to identify existing studies that present the outcomes of each surgical technique. Reinfection rate was the primary outcome measure. Studies of specific subsets of patients such as resistant organisms were excluded.
Results
63 studies were identified that met the inclusion criteria. The majority of which (58) were reports of two-stage revision. Reinfection rated varied between 0% and 41% in two-stage studies, and 0% and 11% in single stage studies. No clinical trials were identified and the majority of studies were observational studies.
Conclusions
Evidence for both one-stage and two-stage revision is largely of low quality. The evidence basis for two-stage revision is significantly larger, and further work into direct comparison between the two techniques should be undertaken as a priority.
doi:10.1186/1471-2474-14-222
PMCID: PMC3734185  PMID: 23895421
Infection; Knee replacement; One stage; Two-stage; Arthroplasty; Revision
8.  DelPhi web server v2: incorporating atomic-style geometrical figures into the computational protocol 
Bioinformatics  2012;28(12):1655-1657.
Summary: A new edition of the DelPhi web server, DelPhi web server v2, is released to include atomic presentation of geometrical figures. These geometrical objects can be used to model nano-size objects together with real biological macromolecules. The position and size of the object can be manipulated by the user in real time until desired results are achieved. The server fixes structural defects, adds hydrogen atoms and calculates electrostatic energies and the corresponding electrostatic potential and ionic distributions.
Availability and implementation: The web server follows a client–server architecture built on PHP and HTML and utilizes DelPhi software. The computation is carried out on supercomputer cluster and results are given back to the user via http protocol, including the ability to visualize the structure and corresponding electrostatic potential via Jmol implementation. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver.
Contact: nsmith@clemson.edu, ealexov@clemson.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/bts200
PMCID: PMC3371833  PMID: 22531215
9.  Genetic Loci for Retinal Arteriolar Microcirculation 
PLoS ONE  2013;8(6):e65804.
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
doi:10.1371/journal.pone.0065804
PMCID: PMC3680438  PMID: 23776548
10.  Genetic variation in F3 (tissue factor) and the risk of incident venous thrombosis: meta-analysis of 8 studies 
doi:10.1111/j.1538-7836.2012.04665.x
PMCID: PMC3397243  PMID: 22340074
Venous thrombosis; tissue factor; F3; D-dimer; epidemiology; meta-analysis
11.  Quercetin Increases CFTR Mediated Chloride Transport and Ciliary Beat Frequency: Therapeutic Implications for Chronic Rhinosinusitis 
Background
Increasing epithelial chloride (Cl−) secretion in the upper airways represents a putative method for promoting MCC through augmentation of airway surface liquid depth. Several naturally occurring flavonoid compounds, including quercetin, have demonstrated the capacity to increase transepithelial Cl− transport. Quercetin exhibits well-known antioxidant and anti-inflammatory activity and is now recognized as a potent activator of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel activity in a fashion largely independent of cAMP signaling. The present study investigates whether this compound activates Cl− secretion and ciliary beat frequency (CBF) in well characterized culture models of sinonasal epithelium.
Methods
CF and non-CF primary human sinonasal (HSNE) and murine nasal septal epithelial (MNSE) cultures were studied for transepithelial ion transport in Ussing chambers under voltage clamp conditions and CBF was performed using pharmacologic manipulation.
Results
Change in short circuit current (ΔISC -expressed as μA/cm2) in response to quercetin were significantly greater than controls in both MNSE (23.23+/−5.44 vs. 2.47 +/− 1.62, p<0.0001) and HSNE (−8.72+/−1.88 vs. −1.88+/−0.66, p<0.01) cultures. CBF was significantly increased in quercetin-treated cells (expressed as fold-change over baseline) in w.t. [1.65+/−0.13 vs. 1.23+/−0.05 (control), p<0.01), but not CFTR−/− (1.65+/−0.29 vs. 1.48+/−0.38, p = 0.23).
Conclusions
Quercetin significantly increased transepithelial Cl− transport and CBF in MNSE and HSNE cultures. Future studies investigating quercetin as a means to promote mucociliary transport in individuals with rhinosinusitis are warranted.
doi:10.2500/ajra.2011.25.3643
PMCID: PMC3584334  PMID: 22186243
12.  Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies 
European Heart Journal  2011;33(2):238-251.
Aims
Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
Methods and results
In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10−23, log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE–APOC1–APOC4–APOC2 cluster [P = 4.9 × 10−30; log Lp-PLA2 difference per allele (beta): −0.054]. There were no significant gene–environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.
Conclusion
Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
doi:10.1093/eurheartj/ehr372
PMCID: PMC3258449  PMID: 22003152
Genome-wide association; Inflammation; Lipoprotein-associated phospholipase A2
13.  Stage-specific expression of protease genes in the apicomplexan parasite, Eimeria tenella 
BMC Genomics  2012;13:685.
Background
Proteases regulate pathogenesis in apicomplexan parasites but investigations of proteases have been largely confined to the asexual stages of Plasmodium falciparum and Toxoplasma gondii. Thus, little is known about proteases in other Apicomplexa, particularly in the sexual stages. We screened the Eimeria tenella genome database for proteases, classified these into families and determined their stage specific expression.
Results
Over forty protease genes were identified in the E. tenella genome. These were distributed across aspartic (three genes), cysteine (sixteen), metallo (fourteen) and serine (twelve) proteases. Expression of at least fifteen protease genes was upregulated in merozoites including homologs of genes known to be important in host cell invasion, remodelling and egress in P. falciparum and/or T. gondii. Thirteen protease genes were specifically expressed or upregulated in gametocytes; five of these were in two families of serine proteases (S1 and S8) that are over-represented in the coccidian parasites, E. tenella and T. gondii, distinctive within the Apicomplexa because of their hard-walled oocysts. Serine protease inhibitors prevented processing of EtGAM56, a protein from E. tenella gametocytes that gives rise to tyrosine-rich peptides that are incorporated into the oocyst wall.
Conclusion
Eimeria tenella possesses a large number of protease genes. Expression of many of these genes is upregulated in asexual stages. However, expression of almost one-third of protease genes is upregulated in, or confined to gametocytes; some of these appear to be unique to the Coccidia and may play key roles in the formation of the oocyst wall, a defining feature of this group of parasites.
doi:10.1186/1471-2164-13-685
PMCID: PMC3770453  PMID: 23216867
Eimeria; Apicomplexa; Protease; Protease inhibitors; Gametocyte; Oocyst wall
14.  Protein Nano-Object Integrator (ProNOI) for generating atomic style objects for molecular modeling 
Background
With the progress of nanotechnology, one frequently has to model biological macromolecules simultaneously with nano-objects. However, the atomic structures of the nano objects are typically not available or they are solid state entities. Because of that, the researchers have to investigate such nano systems by generating models of the nano objects in a manner that the existing software be able to carry the simulations. In addition, it should allow generating composite objects with complex shape by combining basic geometrical figures and embedding biological macromolecules within the system.
Results
Here we report the Protein Nano-Object Integrator (ProNOI) which allows for generating atomic-style geometrical objects with user desired shape and dimensions. Unlimited number of objects can be created and combined with biological macromolecules in Protein Data Bank (PDB) format file. Once the objects are generated, the users can use sliders to manipulate their shape, dimension and absolute position. In addition, the software offers the option to charge the objects with either specified surface or volumetric charge density and to model them with user-desired dielectric constants. According to the user preference, the biological macromolecule atoms can be assigned charges and radii according to four different force fields: Amber, Charmm, OPLS and PARSE. The biological macromolecules and the atomic-style objects are exported as a position, charge and radius (PQR) file, or if a default dielectric constant distribution is not selected, it is exported as a position, charge, radius and epsilon (PQRE) file. As illustration of the capabilities of the ProNOI, we created a composite object in a shape of a robot, aptly named the Clemson Robot, whose parts are charged with various volumetric charge densities and holds the barnase-barstar protein complex in its hand.
Conclusions
The Protein Nano-Object Integrator (ProNOI) is a convenient tool for generating atomic-style nano shapes in conjunction with biological macromolecule(s). Charges and radii on the macromolecule atoms and the atoms in the shapes are assigned according to the user’s preferences allowing various scenarios of modeling. The default output file is in PQR (PQRE) format which is readable by almost any software available in biophysical field. It can be downloaded from: http://compbio.clemson.edu/downloadDir/ProNO_integrator.tar.gz
doi:10.1186/1472-6807-12-31
PMCID: PMC3532097  PMID: 23217202
Biological macromolecules; Electrostatic calculations; Molecular modeling; Nano technology; DelPhi; Poisson-Boltzmann equation
15.  Effect of genetic variations in Syntaxin Binding Protein-5 and Syntaxin-2 on Von Willebrand Factor concentration and cardiovascular risk 
Background
Elevated von Willebrand Factor (VWF) plasma levels are associated with an increased risk of cardiovascular disease. A meta-analysis of genome wide association studies on VWF identified novel candidate genes, i.e. syntaxin-binding protein 5 (STXBP5) and syntaxin 2 (STX2), which are possibly involved in the secretion of VWF. We investigated whether VWF antigen levels (VWF:Ag), VWF collagen-binding activity (VWF:CB), and the risk of arterial thrombosis are affected by common genetic variations in these genes.
Methods and Results
In 463 young Caucasian subjects (males ≤ 45 years, females ≤ 55 years), who were included one to three months after a first event of arterial thrombosis, and 406 controls, we measured VWF:Ag and VWF:CB. Nine haplotype tagging SNPs of STXBP5 and STX2 were selected and subsequently analysed using linear regression with additive genetic models adjusted for age, sex and ABO blood group. The minor alleles of rs9399599 and rs1039084 in STXBP5 were associated with lower VWF plasma levels and activity, whereas the minor allele of rs7978987 in STX2 was associated with higher VWF plasma levels and activity. The minor alleles of the SNPs in STX2 were associated with a reduced risk of arterial thrombosis (rs1236:OR 0.73 [95%CI 0.59, 0.89], rs7978987:OR 0.81 [95%CI 0.65, 1.00], rs11061158:OR 0.69 [95%CI 0.55, 0.88]).
Conclusion
Genetic variability in STXBP5 and STX2 affects both VWF concentration and activity in young individuals with premature arterial thrombosis. Furthermore, in our study genetic variability in STX2 is associated with the risk of arterial thrombosis. However, at this point the underlying mechanism remains unclear.
doi:10.1161/CIRCGENETICS.110.957407
PMCID: PMC3511837  PMID: 21156930
Von Willebrand Factor; genetics; STX2; STXBP5; cardiovascular diseases
16.  Validation of the Normalized Difference Vegetation Index as a measure of neighborhood greenness 
Annals of epidemiology  2011;21(12):946-952.
Purpose
To assess the validity of a GIS measure, the Normalized Difference Vegetation Index (NDVI), as a measure of neighborhood greenness for epidemiologic research.
Methods
Using remote-sensing spectral data, NDVI was calculated for a 100-m radial distance around 124 residences in greater Seattle. The criterion standard was rating of greenness for corresponding residential areas by three environmental psychologists. Pearson correlations and regression models were used to assess the association between the psychologists’ ratings of greenness and NDVI. Analyses were also stratified by residential density to assess whether the correlations differed between low and high density.
Results
Mean NDVI among this sample of residences was .27 (SD = 0.11; range: −.04 to .54), and the mean psychologist rating of greenness was 2.84 (SD = 0.98; range: 1 to 5). The correlation between NDVI and expert ratings of greenness was high (r = .69). The correlation was equivalently strong within each strata of residential density.
Conclusions
NDVI is a useful measure of neighborhood greenness. In addition to showing strong correlation with expert ratings, this measure has practical advantages including availability of data and ease of application to various boundaries which would aid in replication and comparability across studies.
doi:10.1016/j.annepidem.2011.09.001
PMCID: PMC3225119  PMID: 21982129
17.  Fasting and Post-Glucose Load Measures of Insulin Resistance and Risk of Ischemic Stroke in Older Adults 
Background and purpose
Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in non-diabetic older adults.
Methods
Participants were men and women in the Cardiovascular Health Study, aged 65+ and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and fasting and 2-hour post-load insulin and glucose; a lower Gutt index indicates higher insulin resistance.
Results
Analyses included 3,442 participants (42% men) with a mean age of 73. Incidence of ischemic stroke was 9.8 strokes per 1,000 person years. The relative risk (RR) for lowest quartile vs. highest quartile of Gutt index was 1.64 (95% confidence interval: 1.24, 2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile vs. lowest quartile of 2-hour glucose was 1.84 (95% CI: 1.39, 2.42). In contrast, the adjusted RR for highest quartile vs. lowest quartile of fasting insulin was 1.10 (95% CI: 0.84, 1.46).
Conclusions
In non-diabetic older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not fasting insulin, was associated with risk of incident ischemic stroke.
doi:10.1161/STROKEAHA.111.620773
PMCID: PMC3226936  PMID: 21998054
Non-diabetic older adults; Cohort study; Gutt insulin sensitivity index
18.  MAOA promoter methylation and susceptibility to carotid atherosclerosis: role of familial factors in a monozygotic twin sample 
BMC Medical Genetics  2012;13:100.
Background
Atherosclerosis is a complex process involving both genetic and epigenetic factors. The monoamine oxidase A (MAOA) gene regulates the metabolism of key neurotransmitters and has been associated with cardiovascular risk factors. This study investigates whether MAOA promoter methylation is associated with atherosclerosis, and whether this association is confounded by familial factors in a monozygotic (MZ) twin sample.
Methods
We studied 84 monozygotic (MZ) twin pairs drawn from the Vietnam Era Twin Registry. Carotid intima-media thickness (IMT) was measured by ultrasound. DNA methylation in the MAOA promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The association between DNA methylation and IMT was first examined by generalized estimating equation, followed by matched pair analyses to determine whether the association was confounded by familial factors.
Results
When twins were analyzed as individuals, increased methylation level was associated with decreased IMT at four of the seven studied CpG sites. However, this association substantially reduced in the matched pair analyses. Further adjustment for MAOA genotype also considerably attenuated this association.
Conclusions
The association between MAOA promoter methylation and carotid IMT is largely explained by familial factors shared by the twins. Because twins reared together share early life experience, which may leave a long-lasting epigenetic mark, aberrant MAOA methylation may represent an early biomarker for unhealthy familial environment. Clarification of familial factors associated with DNA methylation and early atherosclerosis will provide important information to uncover clinical correlates of disease.
doi:10.1186/1471-2350-13-100
PMCID: PMC3532355  PMID: 23116433
DNA methylation; MAOA; Carotid atherosclerosis; Monozygotic twins; Familial factors
19.  ARN-509: a novel anti-androgen for prostate cancer treatment 
Cancer research  2012;72(6):1494-1503.
Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR-pathway targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor this is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.
doi:10.1158/0008-5472.CAN-11-3948
PMCID: PMC3306502  PMID: 22266222
prostate cancer; castration-resistant prostate cancer; anti-androgen; androgen receptor
20.  A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium 
Human Molecular Genetics  2011;20(17):3525-3534.
Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12–13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
doi:10.1093/hmg/ddr264
PMCID: PMC3153310  PMID: 21676895
21.  Eye movements during visual search in patients with glaucoma 
BMC Ophthalmology  2012;12:45.
Background
Glaucoma has been shown to lead to disability in many daily tasks including visual search. This study aims to determine whether the saccadic eye movements of people with glaucoma differ from those of people with normal vision, and to investigate the association between eye movements and impaired visual search.
Methods
Forty patients (mean age: 67 [SD: 9] years) with a range of glaucomatous visual field (VF) defects in both eyes (mean best eye mean deviation [MD]: –5.9 (SD: 5.4) dB) and 40 age-related people with normal vision (mean age: 66 [SD: 10] years) were timed as they searched for a series of target objects in computer displayed photographs of real world scenes. Eye movements were simultaneously recorded using an eye tracker. Average number of saccades per second, average saccade amplitude and average search duration across trials were recorded. These response variables were compared with measurements of VF and contrast sensitivity.
Results
The average rate of saccades made by the patient group was significantly smaller than the number made by controls during the visual search task (P = 0.02; mean reduction of 5.6% (95% CI: 0.1 to 10.4%). There was no difference in average saccade amplitude between the patients and the controls (P = 0.09). Average number of saccades was weakly correlated with aspects of visual function, with patients with worse contrast sensitivity (PR logCS; Spearman’s rho: 0.42; P = 0.006) and more severe VF defects (best eye MD; Spearman’s rho: 0.34; P = 0.037) tending to make less eye movements during the task. Average detection time in the search task was associated with the average rate of saccades in the patient group (Spearman’s rho = −0.65; P < 0.001) but this was not apparent in the controls.
Conclusions
The average rate of saccades made during visual search by this group of patients was fewer than those made by people with normal vision of a similar average age. There was wide variability in saccade rate in the patients but there was an association between an increase in this measure and better performance in the search task. Assessment of eye movements in individuals with glaucoma might provide insight into the functional deficits of the disease.
doi:10.1186/1471-2415-12-45
PMCID: PMC3505163  PMID: 22937814
Glaucoma; Eye movements; Visual search; Visual disability
22.  Robust spindle alignment in Drosophila neuroblasts by ultrasensitive activation of Pins 
Molecular cell  2011;43(4):540-549.
Cellular signaling pathways exhibit complex response profiles with features such as thresholds and steep activation (i.e. ultrasensitivity). In a reconstituted mitotic spindle orientation pathway, activation of Drosophila Pins (LGN in mammals) by Gαi is ultrasensitive (apparent Hill coefficient of 3.1), such that Pins recruitment of the microtubule-binding protein Mud (NuMA) occurs over a very narrow G αi concentration range. Ultrasensitivity is required for Pins function in neuroblasts as a non-ultrasensitive Pins mutant fails to robustly couple spindle position to cell polarity. Pins contains three Gαi binding GoLoco domains (GLs); Gαi binding to GL3 activates Pins whereas GLs 1 and 2 shape the response profile. Although cooperative binding is one mechanism for generating ultrasensitivity, we find GLs 1 and 2 act as “decoys” that compete against activation at GL3. Many signaling proteins contain multiple protein interaction domains and the decoy mechanism may be a common method for generating ultrasensitivity in regulatory pathways.
doi:10.1016/j.molcel.2011.06.030
PMCID: PMC3161515  PMID: 21855794
23.  Meta-analysis identifies six new susceptibility loci for atrial fibrillation 
Ellinor, Patrick T | Lunetta, Kathryn L | Albert, Christine M | Glazer, Nicole L | Ritchie, Marylyn D | Smith, Albert V | Arking, Dan E | Müller-Nurasyid, Martina | Krijthe, Bouwe P | Lubitz, Steven A | Bis, Joshua C | Chung, Mina K | Dörr, Marcus | Ozaki, Kouichi | Roberts, Jason D | Smith, J Gustav | Pfeufer, Arne | Sinner, Moritz F | Lohman, Kurt | Ding, Jingzhong | Smith, Nicholas L | Smith, Jonathan D | Rienstra, Michiel | Rice, Kenneth M | Van Wagoner, David R | Magnani, Jared W | Wakili, Reza | Clauss, Sebastian | Rotter, Jerome I | Steinbeck, Gerhard | Launer, Lenore J | Davies, Robert W | Borkovich, Matthew | Harris, Tamara B | Lin, Honghuang | Völker, Uwe | Völzke, Henry | Milan, David J | Hofman, Albert | Boerwinkle, Eric | Chen, Lin Y | Soliman, Elsayed Z | Voight, Benjamin F | Li, Guo | Chakravarti, Aravinda | Kubo, Michiaki | Tedrow, Usha B | Rose, Lynda M | Ridker, Paul M | Conen, David | Tsunoda, Tatsuhiko | Furukawa, Tetsushi | Sotoodehnia, Nona | Xu, Siyan | Kamatani, Naoyuki | Levy, Daniel | Nakamura, Yusuke | Parvez, Babar | Mahida, Saagar | Furie, Karen L | Rosand, Jonathan | Muhammad, Raafia | Psaty, Bruce M | Meitinger, Thomas | Perz, Siegfried | Wichmann, H-Erich | Witteman, Jacqueline C M | Kao, W H Linda | Kathiresan, Sekar | Roden, Dan M | Uitterlinden, Andre G | Rivadeneira, Fernando | McKnight, Barbara | Sjögren, Marketa | Newman, Anne B | Liu, Yongmei | Gollob, Michael H | Melander, Olle | Tanaka, Toshihiro | Ch Stricker, Bruno H | Felix, Stephan B | Alonso, Alvaro | Darbar, Dawood | Barnard, John | Chasman, Daniel I | Heckbert, Susan R | Benjamin, Emelia J | Gudnason, Vilmundur | Kääb, Stefan
Nature Genetics  2012;44(6):670-675.
Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death1. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 1 0,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
doi:10.1038/ng.2261
PMCID: PMC3366038  PMID: 22544366
24.  Genome-wide association studies of cerebral white matter lesion burden: the CHARGE Consortium 
Annals of neurology  2011;69(6):928-939.
Objective
White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
Methods
We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
Results
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10−9), rs11869977 (P=5.7×10−9), rs936393 (P=6.8×10−9), rs3744017 (P=7.3×10−9), and rs1055129 (P=4.1×10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample).
Interpretation
This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
doi:10.1002/ana.22403
PMCID: PMC3122147  PMID: 21681796
25.  DelPhi: a comprehensive suite for DelPhi software and associated resources 
BMC Biophysics  2012;5:9.
Background
Accurate modeling of electrostatic potential and corresponding energies becomes increasingly important for understanding properties of biological macromolecules and their complexes. However, this is not an easy task due to the irregular shape of biological entities and the presence of water and mobile ions.
Results
Here we report a comprehensive suite for the well-known Poisson-Boltzmann solver, DelPhi, enriched with additional features to facilitate DelPhi usage. The suite allows for easy download of both DelPhi executable files and source code along with a makefile for local installations. The users can obtain the DelPhi manual and parameter files required for the corresponding investigation. Non-experienced researchers can download examples containing all necessary data to carry out DelPhi runs on a set of selected examples illustrating various DelPhi features and demonstrating DelPhi’s accuracy against analytical solutions.
Conclusions
DelPhi suite offers not only the DelPhi executable and sources files, examples and parameter files, but also provides links to third party developed resources either utilizing DelPhi or providing plugins for DelPhi. In addition, the users and developers are offered a forum to share ideas, resolve issues, report bugs and seek help with respect to the DelPhi package. The resource is available free of charge for academic users from URL: http://compbio.clemson.edu/DelPhi.php.
doi:10.1186/2046-1682-5-9
PMCID: PMC3463482  PMID: 22583952
DelPhi; Poisson-Boltzmann equation; Implicit solvation model; Electrostatics; Biological macromolecules; Software

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