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Find video protocols related to scientific articles indexed in Pubmed.
MUSCLE: Automated Multi-objective Evolutionary Optimisation of Targeted LC-MS/MS Analysis.
Bioinformatics
PUBLISHED: 11-13-2014
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Developing liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses of (bio)chemicals is both time consuming and challenging, largely because of the large number of LC and MS instrument parameters that need to be optimised. This bottleneck significantly impedes our ability to establish new (bio)analytical methods in fields such as pharmacology, metabolomics and pesticide research. We report the development of a multi-platform, user-friendly software tool MUSCLE (Multi-platform Unbiased optimisation of Spectrometry via Closed Loop Experimentation) for the robust and fully-automated multiobjective optimisation of targeted LC-MS/MS analysis. MUSCLE shortened the analysis times and increased the analytical sensitivities of targeted metabolite analysis which was demonstrated on two different manufacturers LC-MS/MS instruments. Availability: Available at http://www.muscleproject.org CONTACT: info@muscleproject.org SUPPLEMENTARY INFORMATION: See Supplementary Data available at the journal's web site.
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Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example.
Front Genet
PUBLISHED: 08-01-2014
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Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.
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Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes.
Diabetes
PUBLISHED: 07-21-2014
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The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (? = 0.018; P = 4 × 10(-29)), lower HDL cholesterol (? = -0.020; P = 7 × 10(-37)), greater hepatic steatosis (? = 0.021; P = 3 × 10(-4)), higher alanine transaminase (? = 0.002; P = 3 × 10(-5)), lower sex-hormone-binding globulin (? = -0.010; P = 9 × 10(-13)), and lower adiponectin (? = -0.015; P = 2 × 10(-26)). The same risk alleles were associated with lower BMI (per-allele ? = -0.008; P = 7 × 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (? = -0.015; P = 6 × 10(-7)). Individuals carrying ?17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10(-13)), CAD (OR 1.12; per-allele P = 1 × 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10(-5)] and 0.67 mmHg [per-allele P = 2 × 10(-4)], respectively) compared with individuals carrying ?9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.
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How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience.
BMJ Open
PUBLISHED: 06-15-2014
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It is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.
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Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.
Am. Heart J.
PUBLISHED: 03-01-2014
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Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.
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Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy.
J. Card. Fail.
PUBLISHED: 01-23-2014
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Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.
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Unexplained Double-Chambered Left Ventricle Associated with Contracting Right Ventricular Aneurysm and Right Atrial Enlargement.
Echocardiography
PUBLISHED: 12-03-2013
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In this article, we describe a double-chambered left ventricle (LV) associated with a functional right ventricular (RV) aneurysm and right atrial (RA) enlargement in an asymptomatic 24-year-old woman with a family history of sudden cardiac death. We will discuss the differential diagnosis, genetic testing and possible prognostic implications.
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
Diabetes
PUBLISHED: 12-02-2013
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Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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Variation in use of left ventriculography in the veterans affairs health care system.
Circ Cardiovasc Qual Outcomes
PUBLISHED: 11-05-2013
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Background- Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System. Methods and Results- We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VAs Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases. Conclusions- There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics.
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Prevalence and Clinical Correlates of Right Ventricular Dysfunction in Patients With Hypertrophic Cardiomyopathy.
Am. J. Cardiol.
PUBLISHED: 07-14-2013
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Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.
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Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
Diabetes
PUBLISHED: 07-08-2013
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Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
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On handling ephemeral resource constraints in evolutionary search.
Evol Comput
PUBLISHED: 06-19-2013
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We consider optimization problems where the set of solutions available for evaluation at any given time t during optimization is some subset of the feasible space. This model is appropriate to describe many closed-loop optimization settings (i.e., where physical processes or experiments are used to evaluate solutions) where, due to resource limitations, it may be impossible to evaluate particular solutions at particular times (despite the solutions being part of the feasible space). We call the constraints determining which solutions are non-evaluable ephemeral resource constraints (ERCs). In this paper, we investigate two specific types of ERC: one encodes periodic resource availabilities, the other models commitment constraints that make the evaluable part of the space a function of earlier evaluations conducted. In an experimental study, both types of constraint are seen to impact the performance of an evolutionary algorithm significantly. To deal with the effects of the ERCs, we propose and test five different constraint-handling policies (adapted from those used to handle standard constraints), using a number of different test functions including a fitness landscape from a real closed-loop problem. We show that knowing information about the type of resource constraint in advance may be sufficient to select an effective policy for dealing with it, even when advance knowledge of the fitness landscape is limited.
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Role of international registries in enhancing the care of familial hypercholesterolaemia.
Int J Evid Based Healthc
PUBLISHED: 06-12-2013
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Familial hypercholesterolaemia (FH) is a relatively common genetic disorder associated with high risk of coronary heart disease that is preventable by early diagnosis and treatment. In a previous article, we reviewed the evidence for clinical management, models of care and health economic evaluations. The present commentary emphasises that collective action is needed to strengthen our approaches to evidence-based care, including better diagnosis and access to effective therapies. We detail how contemporary innovations in inter-operable, web-based, open-source and secure registries can provide the supporting infrastructure to: (i) address a current gap in the flow of data for measuring the quality of healthcare; (ii) support basic research through provision of high-quality, de-identified aggregate data; (iii) enable equitable access to clinical trials; and (iv) support efforts to disseminate evidence for best practice and information for care services. We describe how these aspects of enabling infrastructure will be incorporated into the development of a National FH Registry for Australasia, and proffer that a coordinated response to FH would be enhanced through a global network of inter-operable registries.
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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Marcel den Hoed, Mark Eijgelsheim, Tonu Esko, Bianca J J M Brundel, David S Peal, David M Evans, Ilja M Nolte, Ayellet V Segrè, Hilma Holm, Robert E Handsaker, Harm-Jan Westra, Toby Johnson, Aaron Isaacs, Jian Yang, Alicia Lundby, Jing Hua Zhao, Young Jin Kim, Min Jin Go, Peter Almgren, Murielle Bochud, Gabrielle Boucher, Marilyn C Cornelis, Daniel Gudbjartsson, David Hadley, Pim van der Harst, Caroline Hayward, Martin den Heijer, Wilmar Igl, Anne U Jackson, Zoltan Kutalik, Jian'an Luan, John P Kemp, Kati Kristiansson, Claes Ladenvall, Mattias Lorentzon, May E Montasser, Omer T Njajou, Paul F O'Reilly, Sandosh Padmanabhan, Beate St Pourcain, Tuomo Rankinen, Perttu Salo, Toshiko Tanaka, Nicholas J Timpson, Veronique Vitart, Lindsay Waite, William Wheeler, Weihua Zhang, Harmen H M Draisma, Mary F Feitosa, Kathleen F Kerr, Penelope A Lind, Evelin Mihailov, N Charlotte Onland-Moret, Ci Song, Michael N Weedon, Weijia Xie, Loïc Yengo, Devin Absher, Christine M Albert, Alvaro Alonso, Dan E Arking, Paul I W de Bakker, Beverley Balkau, Cristina Barlassina, Paola Benaglio, Joshua C Bis, Nabila Bouatia-Naji, Søren Brage, Stephen J Chanock, Peter S Chines, Mina Chung, Dawood Darbar, Christian Dina, Marcus Dörr, Paul Elliott, Stephan B Felix, Krista Fischer, Christian Fuchsberger, Eco J C de Geus, Philippe Goyette, Vilmundur Gudnason, Tamara B Harris, Anna-Liisa Hartikainen, Aki S Havulinna, Susan R Heckbert, Andrew A Hicks, Albert Hofman, Suzanne Holewijn, Femke Hoogstra-Berends, Jouke-Jan Hottenga, Majken K Jensen, Asa Johansson, Juhani Junttila, Stefan Kääb, Bart Kanon, Shamika Ketkar, Kay-Tee Khaw, Joshua W Knowles, Angrad S Kooner, Jan A Kors, Meena Kumari, Lili Milani, Päivi Laiho, Edward G Lakatta, Claudia Langenberg, Maarten Leusink, Yongmei Liu, Robert N Luben, Kathryn L Lunetta, Stacey N Lynch, Marcello R P Markus, Pedro Marques-Vidal, Irene Mateo Leach, Wendy L McArdle, Steven A McCarroll, Sarah E Medland, Kathryn A Miller, Grant W Montgomery, Alanna C Morrison, Martina Müller-Nurasyid, Pau Navarro, Mari Nelis, Jeffrey R O'Connell, Christopher J O'Donnell, Ken K Ong, Anne B Newman, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Bruce M Psaty, Dabeeru C Rao, Susan M Ring, Elizabeth J Rossin, Diana Rudan, Serena Sanna, Robert A Scott, Jaban S Sehmi, Stephen Sharp, Jordan T Shin, Andrew B Singleton, Albert V Smith, Nicole Soranzo, Tim D Spector, Chip Stewart, Heather M Stringham, Kirill V Tarasov, André G Uitterlinden, Liesbeth Vandenput, Shih-Jen Hwang, John B Whitfield, Cisca Wijmenga, Sarah H Wild, Gonneke Willemsen, James F Wilson, Jacqueline C M Witteman, Andrew Wong, Quenna Wong, Yalda Jamshidi, Paavo Zitting, Jolanda M A Boer, Dorret I Boomsma, Ingrid B Borecki, Cornelia M van Duijn, Ulf Ekelund, Nita G Forouhi, Philippe Froguel, Aroon Hingorani, Erik Ingelsson, Mika Kivimäki, Richard A Kronmal, Diana Kuh, Lars Lind, Nicholas G Martin, Ben A Oostra, Nancy L Pedersen, Thomas Quertermous, Jerome I Rotter, Yvonne T van der Schouw, W M Monique Verschuren, Mark Walker, Demetrius Albanes, David O Arnar, Themistocles L Assimes, Stefania Bandinelli, Michael Boehnke, Rudolf A de Boer, Claude Bouchard, W L Mark Caulfield, John C Chambers, Gary Curhan, Daniele Cusi, Johan Eriksson, Luigi Ferrucci, Wiek H van Gilst, Nicola Glorioso, Jacqueline de Graaf, Leif Groop, Ulf Gyllensten, Wen-Chi Hsueh, Frank B Hu, Heikki V Huikuri, David J Hunter, Carlos Iribarren, Bo Isomaa, Marjo-Riitta Järvelin, Antti Jula, Mika Kähönen, Lambertus A Kiemeney, Melanie M van der Klauw, Jaspal S Kooner, Peter Kraft, Licia Iacoviello, Terho Lehtimäki, Marja-Liisa L Lokki, Braxton D Mitchell, Gerjan Navis, Markku S Nieminen, Claes Ohlsson, Neil R Poulter, Lu Qi, Olli T Raitakari, Eric B Rimm, John D Rioux, Federica Rizzi, Igor Rudan, Veikko Salomaa, Peter S Sever, Denis C Shields, Alan R Shuldiner, Juha Sinisalo, Alice V Stanton, Ronald P Stolk, David P Strachan, Jean-Claude Tardif, Unnur Thorsteinsdottir, Jaako Tuomilehto, Dirk J van Veldhuisen, Jarmo Virtamo, Jorma Viikari, Peter Vollenweider, Gérard Waeber, Elisabeth Widén, Yoon Shin Cho, Jesper V Olsen, Peter M Visscher, Cristen Willer, Lude Franke, , Jeanette Erdmann, John R Thompson, Arne Pfeufer, Nona Sotoodehnia, Christopher Newton-Cheh, Patrick T Ellinor, Bruno H Ch Stricker, Andres Metspalu, Markus Perola, Jacques S Beckmann, George Davey Smith, Kari Stefansson, Nicholas J Wareham, Patricia B Munroe, Ody C M Sibon, David J Milan, Harold Snieder, Nilesh J Samani, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 03-21-2013
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Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
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Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity.
Circulation
PUBLISHED: 03-21-2013
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Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.
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Accuracy and tractability of a kriging model of intramolecular polarizable multipolar electrostatics and its application to histidine.
J Comput Chem
PUBLISHED: 03-18-2013
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We propose a generic method to model polarization in the context of high-rank multipolar electrostatics. This method involves the machine learning technique kriging, here used to capture the response of an atomic multipole moment of a given atom to a change in the positions of the atoms surrounding this atom. The atoms are malleable boxes with sharp boundaries, they do not overlap and exhaust space. The method is applied to histidine where it is able to predict atomic multipole moments (up to hexadecapole) for unseen configurations, after training on 600 geometries distorted using normal modes of each of its 24 local energy minima at B3LYP/apc-1 level. The quality of the predictions is assessed by calculating the Coulomb energy between an atom for which the moments have been predicted and the surrounding atoms (having exact moments). Only interactions between atoms separated by three or more bonds ("1, 4 and higher" interactions) are included in this energy error. This energy is compared with that of a central atom with exact multipole moments interacting with the same environment. The resulting energy discrepancies are summed for 328 atom-atom interactions, for each of the 29 atoms of histidine being a central atom in turn. For 80% of the 539 test configurations (outside the training set), this summed energy deviates by less than 1 kcal mol(-1).
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Trans-ethnic fine mapping identifies a novel independent locus at the 3 end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population.
Diabetologia
PUBLISHED: 02-27-2013
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Candidate gene and genome-wide association studies have identified ?60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.
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Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.
Diabetes
PUBLISHED: 02-01-2013
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Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.
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Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations.
Am. J. Hum. Genet.
PUBLISHED: 01-18-2013
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Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Womens Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.
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The dual role of fragments in fragment-assembly methods for de novo protein structure prediction.
Proteins
PUBLISHED: 07-05-2011
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In fragment-assembly techniques for protein structure prediction, models of protein structure are assembled from fragments of known protein structures. This process is typically guided by a knowledge-based energy function and uses a heuristic optimization method. The fragments play two important roles in this process: they define the set of structural parameters available, and they also assume the role of the main variation operators that are used by the optimiser. Previous analysis has typically focused on the first of these roles. In particular, the relationship between local amino acid sequence and local protein structure has been studied by a range of authors. The correlation between the two has been shown to vary with the window length considered, and the results of these analyses have informed directly the choice of fragment length in state-of-the-art prediction techniques. Here, we focus on the second role of fragments and aim to determine the effect of fragment length from an optimization perspective. We use theoretical analyses to reveal how the size and structure of the search space changes as a function of insertion length. Furthermore, empirical analyses are used to explore additional ways in which the size of the fragment insertion influences the search both in a simulation model and for the fragment-assembly technique, Rosetta. Proteins 2011. © 2011 Wiley Periodicals, Inc.
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Phased whole-genome genetic risk in a family quartet using a major allele reference sequence.
PLoS Genet.
PUBLISHED: 04-21-2011
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Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.
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Efficient discovery of anti-inflammatory small-molecule combinations using evolutionary computing.
Nat. Chem. Biol.
PUBLISHED: 04-12-2011
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The control of biochemical fluxes is distributed, and to perturb complex intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations leads to a combinatorial explosion in the number of experiments that would have to be performed in a complete analysis. We used a multiobjective evolutionary algorithm to optimize reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-1? expression. The evolutionary algorithm converged on excellent solutions within 11 generations, during which we studied just 550 combinations out of the potential search space of ~9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the evolutionary algorithm were then optimized pairwise. A p38 MAPK inhibitor together with either an inhibitor of I?B kinase or a chelator of poorly liganded iron yielded synergistic inhibition of macrophage IL-1? expression. Evolutionary searches provide a powerful and general approach to the discovery of new combinations of pharmacological agents with therapeutic indices potentially greater than those of single drugs.
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A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.
Diabetes
PUBLISHED: 03-08-2011
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OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ?2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ?9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
Heribert Schunkert, Inke R König, Sekar Kathiresan, Muredach P Reilly, Themistocles L Assimes, Hilma Holm, Michael Preuss, Alexandre F R Stewart, Maja Barbalic, Christian Gieger, Devin Absher, Zouhair Aherrahrou, Hooman Allayee, David Altshuler, Sonia S Anand, Karl Andersen, Jeffrey L Anderson, Diego Ardissino, Stephen G Ball, Anthony J Balmforth, Timothy A Barnes, Diane M Becker, Lewis C Becker, Klaus Berger, Joshua C Bis, S Matthijs Boekholdt, Eric Boerwinkle, Peter S Braund, Morris J Brown, Mary Susan Burnett, Ian Buysschaert, , John F Carlquist, Li Chen, Sven Cichon, Veryan Codd, Robert W Davies, George Dedoussis, Abbas Dehghan, Serkalem Demissie, Joseph M Devaney, Patrick Diemert, Ron Do, Angela Doering, Sandra Eifert, Nour Eddine El Mokhtari, Stephen G Ellis, Roberto Elosua, James C Engert, Stephen E Epstein, Ulf de Faire, Marcus Fischer, Aaron R Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Vilmundur Gudnason, Jeffrey R Gulcher, Eran Halperin, Naomi Hammond, Stanley L Hazen, Albert Hofman, Benjamin D Horne, Thomas Illig, Carlos Iribarren, Gregory T Jones, J Wouter Jukema, Michael A Kaiser, Lee M Kaplan, John J P Kastelein, Kay-Tee Khaw, Joshua W Knowles, Genovefa Kolovou, Augustine Kong, Reijo Laaksonen, Diether Lambrechts, Karin Leander, Guillaume Lettre, Mingyao Li, Wolfgang Lieb, Christina Loley, Andrew J Lotery, Pier M Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P McKeown, Christa Meisinger, Thomas Meitinger, Olle Melander, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W Mühleisen, Joseph B Muhlestein, Thomas Münzel, Kiran Musunuru, Janja Nahrstaedt, Christopher P Nelson, Markus M Nöthen, Oliviero Olivieri, Riyaz S Patel, Chris C Patterson, Annette Peters, Flora Peyvandi, Liming Qu, Arshed A Quyyumi, Daniel J Rader, Loukianos S Rallidis, Catherine Rice, Frits R Rosendaal, Diana Rubin, Veikko Salomaa, M Lourdes Sampietro, Manj S Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M Schwartz, David S Siscovick, Mohan Sivananthan, Suthesh Sivapalaratnam, Albert Smith, Tamara B Smith, Jaapjan D Snoep, Nicole Soranzo, John A Spertus, Klaus Stark, Kathy Stirrups, Monika Stoll, W H Wilson Tang, Stephanie Tennstedt, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Maciej Tomaszewski, André G Uitterlinden, Andre M van Rij, Benjamin F Voight, Nick J Wareham, George A Wells, H-Erich Wichmann, Philipp S Wild, Christina Willenborg, Jaqueline C M Witteman, Benjamin J Wright, Shu Ye, Tanja Zeller, Andreas Ziegler, Francois Cambien, Alison H Goodall, L Adrienne Cupples, Thomas Quertermous, Winfried März, Christian Hengstenberg, Stefan Blankenberg, Willem H Ouwehand, Alistair S Hall, Panos Deloukas, John R Thompson, Kari Stefansson, Robert Roberts, Unnur Thorsteinsdottir, Christopher J O'Donnell, Ruth McPherson, Jeanette Erdmann, Nilesh J Samani.
Nat. Genet.
PUBLISHED: 02-10-2011
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We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10?? and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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Predictive models for population performance on real biological fitness landscapes.
Bioinformatics
PUBLISHED: 07-17-2010
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Directed evolution, in addition to its principal application of obtaining novel biomolecules, offers significant potential as a vehicle for obtaining useful information about the topologies of biomolecular fitness landscapes. In this article, we make use of a special type of model of fitness landscapes-based on finite state machines-which can be inferred from directed evolution experiments. Importantly, the model is constructed only from the fitness data and phylogeny, not sequence or structural information, which is often absent. The model, called a landscape state machine (LSM), has already been used successfully in the evolutionary computation literature to model the landscapes of artificial optimization problems. Here, we use the method for the first time to simulate a biological fitness landscape based on experimental evaluation.
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Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.
Themistocles L Assimes, Hilma Holm, Sekar Kathiresan, Muredach P Reilly, Gudmar Thorleifsson, Benjamin F Voight, Jeanette Erdmann, Christina Willenborg, Dhananjay Vaidya, Changchun Xie, Chris C Patterson, Thomas M Morgan, Mary Susan Burnett, Mingyao Li, Mark A Hlatky, Joshua W Knowles, John R Thompson, Devin Absher, Carlos Iribarren, Alan Go, Stephen P Fortmann, Stephen Sidney, Neil Risch, Hua Tang, Richard M Myers, Klaus Berger, Monika Stoll, Svati H Shah, Gudmundur Thorgeirsson, Karl Andersen, Aki S Havulinna, J Enrique Herrera, Nauder Faraday, Yoonhee Kim, Brian G Kral, Rasika A Mathias, Ingo Ruczinski, Bhoom Suktitipat, Alexander F Wilson, Lisa R Yanek, Lewis C Becker, Patrick Linsel-Nitschke, Wolfgang Lieb, Inke R König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Wibke Reinhard, Janina Winogradow, Martina Grassl, Anika Grosshennig, Michael Preuss, Stefan Schreiber, H-Erich Wichmann, Christa Meisinger, Jean Yee, Yechiel Friedlander, Ron Do, James B Meigs, Gordon Williams, David M Nathan, Calum A MacRae, Liming Qu, Robert L Wilensky, William H Matthai, Atif N Qasim, Hakon Hakonarson, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent E Mooser, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, Nicola Martinelli, Oliviero Olivieri, Elisabetta Trabetti, Giovanni Malerba, Pier Franco Pignatti, Candace Guiducci, Daniel Mirel, Melissa Parkin, Joel N Hirschhorn, Rosanna Asselta, Stefano Duga, Kiran Musunuru, Mark J Daly, Shaun Purcell, Sandra Eifert, Peter S Braund, Benjamin J Wright, Anthony J Balmforth, Stephen G Ball, , Willem H Ouwehand, Panos Deloukas, Michael Scholz, Francois Cambien, Andreas Huge, Thomas Scheffold, Veikko Salomaa, Domenico Girelli, Christopher B Granger, Leena Peltonen, Pascal P McKeown, David Altshuler, Olle Melander, Joseph M Devaney, Stephen E Epstein, Daniel J Rader, Roberto Elosua, James C Engert, Sonia S Anand, Alistair S Hall, Andreas Ziegler, Christopher J O'Donnell, John A Spertus, David Siscovick, Stephen M Schwartz, Diane Becker, Unnur Thorsteinsdottir, Kari Stefansson, Heribert Schunkert, Nilesh J Samani, Thomas Quertermous.
J. Am. Coll. Cardiol.
PUBLISHED: 06-14-2010
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We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
Elizabeth K Speliotes, Cristen J Willer, Sonja I Berndt, Keri L Monda, Gudmar Thorleifsson, Anne U Jackson, Hana Lango Allen, Cecilia M Lindgren, Jian'an Luan, Reedik Mägi, Joshua C Randall, Sailaja Vedantam, Thomas W Winkler, Lu Qi, Tsegaselassie Workalemahu, Iris M Heid, Valgerdur Steinthorsdottir, Heather M Stringham, Michael N Weedon, Eleanor Wheeler, Andrew R Wood, Teresa Ferreira, Robert J Weyant, Ayellet V Segrè, Karol Estrada, Liming Liang, James Nemesh, Ju-Hyun Park, Stefan Gustafsson, Tuomas O Kilpeläinen, Jian Yang, Nabila Bouatia-Naji, Tonu Esko, Mary F Feitosa, Zoltan Kutalik, Massimo Mangino, Soumya Raychaudhuri, André Scherag, Albert Vernon Smith, Ryan Welch, Jing Hua Zhao, Katja K Aben, Devin M Absher, Najaf Amin, Anna L Dixon, Eva Fisher, Nicole L Glazer, Michael E Goddard, Nancy L Heard-Costa, Volker Hoesel, Jouke-Jan Hottenga, Asa Johansson, Toby Johnson, Shamika Ketkar, Claudia Lamina, Shengxu Li, Miriam F Moffatt, Richard H Myers, Narisu Narisu, John R B Perry, Marjolein J Peters, Michael Preuss, Samuli Ripatti, Fernando Rivadeneira, Camilla Sandholt, Laura J Scott, Nicholas J Timpson, Jonathan P Tyrer, Sophie van Wingerden, Richard M Watanabe, Charles C White, Fredrik Wiklund, Christina Barlassina, Daniel I Chasman, Matthew N Cooper, John-Olov Jansson, Robert W Lawrence, Niina Pellikka, Inga Prokopenko, Jianxin Shi, Elisabeth Thiering, Helene Alavere, Maria T S Alibrandi, Peter Almgren, Alice M Arnold, Thor Aspelund, Larry D Atwood, Beverley Balkau, Anthony J Balmforth, Amanda J Bennett, Yoav Ben-Shlomo, Richard N Bergman, Sven Bergmann, Heike Biebermann, Alexandra I F Blakemore, Tanja Boes, Lori L Bonnycastle, Stefan R Bornstein, Morris J Brown, Thomas A Buchanan, Fabio Busonero, Harry Campbell, Francesco P Cappuccio, Christine Cavalcanti-Proença, Yii-Der Ida Chen, Chih-Mei Chen, Peter S Chines, Robert Clarke, Lachlan Coin, John Connell, Ian N M Day, Martin den Heijer, Jubao Duan, Shah Ebrahim, Paul Elliott, Roberto Elosua, Gudny Eiriksdottir, Michael R Erdos, Johan G Eriksson, Maurizio F Facheris, Stephan B Felix, Pamela Fischer-Posovszky, Aaron R Folsom, Nele Friedrich, Nelson B Freimer, Mao Fu, Stefan Gaget, Pablo V Gejman, Eco J C Geus, Christian Gieger, Anette P Gjesing, Anuj Goel, Philippe Goyette, Harald Grallert, Jürgen Gräßler, Danielle M Greenawalt, Christopher J Groves, Vilmundur Gudnason, Candace Guiducci, Anna-Liisa Hartikainen, Neelam Hassanali, Alistair S Hall, Aki S Havulinna, Caroline Hayward, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Anke Hinney, Albert Hofman, Georg Homuth, Jennie Hui, Wilmar Igl, Carlos Iribarren, Bo Isomaa, Kevin B Jacobs, Ivonne Jarick, Elizabeth Jewell, Ulrich John, Torben Jørgensen, Pekka Jousilahti, Antti Jula, Marika Kaakinen, Eero Kajantie, Lee M Kaplan, Sekar Kathiresan, Johannes Kettunen, Leena Kinnunen, Joshua W Knowles, Ivana Kolčić, Inke R König, Seppo Koskinen, Peter Kovacs, Johanna Kuusisto, Peter Kraft, Kirsti Kvaløy, Jaana Laitinen, Olivier Lantieri, Chiara Lanzani, Lenore J Launer, Cécile Lecoeur, Terho Lehtimäki, Guillaume Lettre, Jianjun Liu, Marja-Liisa Lokki, Mattias Lorentzon, Robert N Luben, Barbara Ludwig, , Paolo Manunta, Diana Marek, Michel Marre, Nicholas G Martin, Wendy L McArdle, Anne McCarthy, Barbara McKnight, Thomas Meitinger, Olle Melander, David Meyre, Kristian Midthjell, Grant W Montgomery, Mario A Morken, Andrew P Morris, Rosanda Mulić, Julius S Ngwa, Mari Nelis, Matt J Neville, Dale R Nyholt, Christopher J O'Donnell, Stephen O'Rahilly, Ken K Ong, Ben Oostra, Guillaume Paré, Alex N Parker, Markus Perola, Irene Pichler, Kirsi H Pietiläinen, Carl G P Platou, Ozren Polašek, Anneli Pouta, Suzanne Rafelt, Olli Raitakari, Nigel W Rayner, Martin Ridderstråle, Winfried Rief, Aimo Ruokonen, Neil R Robertson, Peter Rzehak, Veikko Salomaa, Alan R Sanders, Manjinder S Sandhu, Serena Sanna, Jouko Saramies, Markku J Savolainen, Susann Scherag, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, Kaisa Silander, Juha Sinisalo, David S Siscovick, Jan H Smit, Nicole Soranzo, Ulla Sovio, Jonathan Stephens, Ida Surakka, Amy J Swift, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Tanya M Teslovich, John R Thompson, Brian Thomson, Anke Tönjes, Tiinamaija Tuomi, Joyce B J van Meurs, Gert-Jan van Ommen, Vincent Vatin, Jorma Viikari, Sophie Visvikis-Siest, Veronique Vitart, Carla I G Vogel, Benjamin F Voight, Lindsay L Waite, Henri Wallaschofski, G Bragi Walters, Elisabeth Widén, Susanna Wiegand, Sarah H Wild, Gonneke Willemsen, Daniel R Witte, Jacqueline C Witteman, Jianfeng Xu, Qunyuan Zhang, Lina Zgaga, Andreas Ziegler, Paavo Zitting, John P Beilby, I Sadaf Farooqi, Johannes Hebebrand, Heikki V Huikuri, Alan L James, Mika Kähönen, Douglas F Levinson, Fabio Macciardi, Markku S Nieminen, Claes Ohlsson, Lyle J Palmer, Paul M Ridker, Michael Stumvoll, Jacques S Beckmann, Heiner Boeing, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, Francis S Collins, L Adrienne Cupples, George Davey Smith, Jeanette Erdmann, Philippe Froguel, Henrik Grönberg, Ulf Gyllensten, Per Hall, Torben Hansen, Tamara B Harris, Andrew T Hattersley, Richard B Hayes, Joachim Heinrich, Frank B Hu, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Jaakko Kaprio, Fredrik Karpe, Kay-Tee Khaw, Lambertus A Kiemeney, Heiko Krude, Markku Laakso, Debbie A Lawlor, Andres Metspalu, Patricia B Munroe, Willem H Ouwehand, Oluf Pedersen, Brenda W Penninx, Annette Peters, Peter P Pramstaller, Thomas Quertermous, Thomas Reinehr, Aila Rissanen, Igor Rudan, Nilesh J Samani, Peter E H Schwarz, Alan R Shuldiner, Timothy D Spector, Jaakko Tuomilehto, Manuela Uda, André Uitterlinden, Timo T Valle, Martin Wabitsch, Gérard Waeber, Nicholas J Wareham, Hugh Watkins, James F Wilson, Alan F Wright, M Carola Zillikens, Nilanjan Chatterjee, Steven A McCarroll, Shaun Purcell, Eric E Schadt, Peter M Visscher, Themistocles L Assimes, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Leif C Groop, Talin Haritunians, David J Hunter, Robert C Kaplan, Karen L Mohlke, Jeffrey R O'Connell, Leena Peltonen, David Schlessinger, David P Strachan, Cornelia M van Duijn, H-Erich Wichmann, Timothy M Frayling, Unnur Thorsteinsdottir, Gonçalo R Abecasis, Inês Barroso, Michael Boehnke, Kari Stefansson, Kari E North, Mark I McCarthy, Joel N Hirschhorn, Erik Ingelsson, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 05-13-2010
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Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ? 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
Iris M Heid, Anne U Jackson, Joshua C Randall, Thomas W Winkler, Lu Qi, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, M Carola Zillikens, Elizabeth K Speliotes, Reedik Mägi, Tsegaselassie Workalemahu, Charles C White, Nabila Bouatia-Naji, Tamara B Harris, Sonja I Berndt, Erik Ingelsson, Cristen J Willer, Michael N Weedon, Jian'an Luan, Sailaja Vedantam, Tonu Esko, Tuomas O Kilpeläinen, Zoltan Kutalik, Shengxu Li, Keri L Monda, Anna L Dixon, Christopher C Holmes, Lee M Kaplan, Liming Liang, Josine L Min, Miriam F Moffatt, Cliona Molony, George Nicholson, Eric E Schadt, Krina T Zondervan, Mary F Feitosa, Teresa Ferreira, Hana Lango Allen, Robert J Weyant, Eleanor Wheeler, Andrew R Wood, , Karol Estrada, Michael E Goddard, Guillaume Lettre, Massimo Mangino, Dale R Nyholt, Shaun Purcell, Albert Vernon Smith, Peter M Visscher, Jian Yang, Steven A McCarroll, James Nemesh, Benjamin F Voight, Devin Absher, Najaf Amin, Thor Aspelund, Lachlan Coin, Nicole L Glazer, Caroline Hayward, Nancy L Heard-Costa, Jouke-Jan Hottenga, Asa Johansson, Toby Johnson, Marika Kaakinen, Karen Kapur, Shamika Ketkar, Joshua W Knowles, Peter Kraft, Aldi T Kraja, Claudia Lamina, Michael F Leitzmann, Barbara McKnight, Andrew P Morris, Ken K Ong, John R B Perry, Marjolein J Peters, Ozren Polašek, Inga Prokopenko, Nigel W Rayner, Samuli Ripatti, Fernando Rivadeneira, Neil R Robertson, Serena Sanna, Ulla Sovio, Ida Surakka, Alexander Teumer, Sophie van Wingerden, Veronique Vitart, Jing Hua Zhao, Christine Cavalcanti-Proença, Peter S Chines, Eva Fisher, Jennifer R Kulzer, Cécile Lecoeur, Narisu Narisu, Camilla Sandholt, Laura J Scott, Kaisa Silander, Klaus Stark, Mari-Liis Tammesoo, Tanya M Teslovich, Nicholas John Timpson, Richard M Watanabe, Ryan Welch, Daniel I Chasman, Matthew N Cooper, John-Olov Jansson, Johannes Kettunen, Robert W Lawrence, Niina Pellikka, Markus Perola, Liesbeth Vandenput, Helene Alavere, Peter Almgren, Larry D Atwood, Amanda J Bennett, Reiner Biffar, Lori L Bonnycastle, Stefan R Bornstein, Thomas A Buchanan, Harry Campbell, Ian N M Day, Mariano Dei, Marcus Dörr, Paul Elliott, Michael R Erdos, Johan G Eriksson, Nelson B Freimer, Mao Fu, Stefan Gaget, Eco J C Geus, Anette P Gjesing, Harald Grallert, Jürgen Gräßler, Christopher J Groves, Candace Guiducci, Anna-Liisa Hartikainen, Neelam Hassanali, Aki S Havulinna, Karl-Heinz Herzig, Andrew A Hicks, Jennie Hui, Wilmar Igl, Pekka Jousilahti, Antti Jula, Eero Kajantie, Leena Kinnunen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Heyo K Kroemer, Vjekoslav Krželj, Johanna Kuusisto, Kirsti Kvaloy, Jaana Laitinen, Olivier Lantieri, G Mark Lathrop, Marja-Liisa Lokki, Robert N Luben, Barbara Ludwig, Wendy L McArdle, Anne McCarthy, Mario A Morken, Mari Nelis, Matt J Neville, Guillaume Paré, Alex N Parker, John F Peden, Irene Pichler, Kirsi H Pietiläinen, Carl G P Platou, Anneli Pouta, Martin Ridderstråle, Nilesh J Samani, Jouko Saramies, Juha Sinisalo, Jan H Smit, Rona J Strawbridge, Heather M Stringham, Amy J Swift, Maris Teder-Laving, Brian Thomson, Gianluca Usala, Joyce B J van Meurs, Gert-Jan van Ommen, Vincent Vatin, Claudia B Volpato, Henri Wallaschofski, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Daniel R Witte, Lina Zgaga, Paavo Zitting, John P Beilby, Alan L James, Mika Kähönen, Terho Lehtimäki, Markku S Nieminen, Claes Ohlsson, Lyle J Palmer, Olli Raitakari, Paul M Ridker, Michael Stumvoll, Anke Tönjes, Jorma Viikari, Beverley Balkau, Yoav Ben-Shlomo, Richard N Bergman, Heiner Boeing, George Davey Smith, Shah Ebrahim, Philippe Froguel, Torben Hansen, Christian Hengstenberg, Kristian Hveem, Bo Isomaa, Torben Jørgensen, Fredrik Karpe, Kay-Tee Khaw, Markku Laakso, Debbie A Lawlor, Michel Marre, Thomas Meitinger, Andres Metspalu, Kristian Midthjell, Oluf Pedersen, Veikko Salomaa, Peter E H Schwarz, Tiinamaija Tuomi, Jaakko Tuomilehto, Timo T Valle, Nicholas J Wareham, Alice M Arnold, Jacques S Beckmann, Sven Bergmann, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Francis S Collins, Gudny Eiriksdottir, Vilmundur Gudnason, Ulf Gyllensten, Anders Hamsten, Andrew T Hattersley, Albert Hofman, Frank B Hu, Thomas Illig, Carlos Iribarren, Marjo-Riitta Järvelin, W H Linda Kao, Jaakko Kaprio, Lenore J Launer, Patricia B Munroe, Ben Oostra, Brenda W Penninx, Peter P Pramstaller, Bruce M Psaty, Thomas Quertermous, Aila Rissanen, Igor Rudan, Alan R Shuldiner, Nicole Soranzo, Timothy D Spector, Ann-Christine Syvänen, Manuela Uda, André Uitterlinden, Henry Völzke, Peter Vollenweider, James F Wilson, Jacqueline C Witteman, Alan F Wright, Gonçalo R Abecasis, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Timothy M Frayling, Leif C Groop, Talin Haritunians, David J Hunter, Robert C Kaplan, Kari E North, Jeffrey R O'Connell, Leena Peltonen, David Schlessinger, David P Strachan, Joel N Hirschhorn, Themistocles L Assimes, H-Erich Wichmann, Unnur Thorsteinsdottir, Cornelia M van Duijn, Kari Stefansson, L Adrienne Cupples, Ruth J F Loos, Inês Barroso, Mark I McCarthy, Caroline S Fox, Karen L Mohlke, Cecilia M Lindgren.
Nat. Genet.
PUBLISHED: 05-06-2010
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Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10?? to P = 1.8 × 10???) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10?³ to P = 1.2 × 10?¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Hana Lango Allen, Karol Estrada, Guillaume Lettre, Sonja I Berndt, Michael N Weedon, Fernando Rivadeneira, Cristen J Willer, Anne U Jackson, Sailaja Vedantam, Soumya Raychaudhuri, Teresa Ferreira, Andrew R Wood, Robert J Weyant, Ayellet V Segrè, Elizabeth K Speliotes, Eleanor Wheeler, Nicole Soranzo, Ju-Hyun Park, Jian Yang, Daniel Gudbjartsson, Nancy L Heard-Costa, Joshua C Randall, Lu Qi, Albert Vernon Smith, Reedik Mägi, Tomi Pastinen, Liming Liang, Iris M Heid, Jian'an Luan, Gudmar Thorleifsson, Thomas W Winkler, Michael E Goddard, Ken Sin Lo, Cameron Palmer, Tsegaselassie Workalemahu, Yurii S Aulchenko, Asa Johansson, M Carola Zillikens, Mary F Feitosa, Tonu Esko, Toby Johnson, Shamika Ketkar, Peter Kraft, Massimo Mangino, Inga Prokopenko, Devin Absher, Eva Albrecht, Florian Ernst, Nicole L Glazer, Caroline Hayward, Jouke-Jan Hottenga, Kevin B Jacobs, Joshua W Knowles, Zoltan Kutalik, Keri L Monda, Ozren Polašek, Michael Preuss, Nigel W Rayner, Neil R Robertson, Valgerdur Steinthorsdottir, Jonathan P Tyrer, Benjamin F Voight, Fredrik Wiklund, Jianfeng Xu, Jing Hua Zhao, Dale R Nyholt, Niina Pellikka, Markus Perola, John R B Perry, Ida Surakka, Mari-Liis Tammesoo, Elizabeth L Altmaier, Najaf Amin, Thor Aspelund, Tushar Bhangale, Gabrielle Boucher, Daniel I Chasman, Constance Chen, Lachlan Coin, Matthew N Cooper, Anna L Dixon, Quince Gibson, Elin Grundberg, Ke Hao, M Juhani Junttila, Lee M Kaplan, Johannes Kettunen, Inke R König, Tony Kwan, Robert W Lawrence, Douglas F Levinson, Mattias Lorentzon, Barbara McKnight, Andrew P Morris, Martina Müller, Julius Suh Ngwa, Shaun Purcell, Suzanne Rafelt, Rany M Salem, Erika Salvi, Serena Sanna, Jianxin Shi, Ulla Sovio, John R Thompson, Michael C Turchin, Liesbeth Vandenput, Dominique J Verlaan, Veronique Vitart, Charles C White, Andreas Ziegler, Peter Almgren, Anthony J Balmforth, Harry Campbell, Lorena Citterio, Alessandro De Grandi, Anna Dominiczak, Jubao Duan, Paul Elliott, Roberto Elosua, Johan G Eriksson, Nelson B Freimer, Eco J C Geus, Nicola Glorioso, Shen Haiqing, Anna-Liisa Hartikainen, Aki S Havulinna, Andrew A Hicks, Jennie Hui, Wilmar Igl, Thomas Illig, Antti Jula, Eero Kajantie, Tuomas O Kilpeläinen, Markku Koiranen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Jaana Laitinen, Jianjun Liu, Marja-Liisa Lokki, Ana Marušić, Andrea Maschio, Thomas Meitinger, Antonella Mulas, Guillaume Paré, Alex N Parker, John F Peden, Astrid Petersmann, Irene Pichler, Kirsi H Pietiläinen, Anneli Pouta, Martin Ridderstråle, Jerome I Rotter, Jennifer G Sambrook, Alan R Sanders, Carsten Oliver Schmidt, Juha Sinisalo, Jan H Smit, Heather M Stringham, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Laura Zagato, Lina Zgaga, Paavo Zitting, Helene Alavere, Martin Farrall, Wendy L McArdle, Mari Nelis, Marjolein J Peters, Samuli Ripatti, Joyce B J van Meurs, Katja K Aben, Kristin G Ardlie, Jacques S Beckmann, John P Beilby, Richard N Bergman, Sven Bergmann, Francis S Collins, Daniele Cusi, Martin den Heijer, Gudny Eiriksdottir, Pablo V Gejman, Alistair S Hall, Anders Hamsten, Heikki V Huikuri, Carlos Iribarren, Mika Kähönen, Jaakko Kaprio, Sekar Kathiresan, Lambertus Kiemeney, Thomas Kocher, Lenore J Launer, Terho Lehtimäki, Olle Melander, Tom H Mosley, Arthur W Musk, Markku S Nieminen, Christopher J O'Donnell, Claes Ohlsson, Ben Oostra, Lyle J Palmer, Olli Raitakari, Paul M Ridker, John D Rioux, Aila Rissanen, Carlo Rivolta, Heribert Schunkert, Alan R Shuldiner, David S Siscovick, Michael Stumvoll, Anke Tönjes, Jaakko Tuomilehto, Gert-Jan van Ommen, Jorma Viikari, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael A Province, Manfred Kayser, Alice M Arnold, Larry D Atwood, Eric Boerwinkle, Stephen J Chanock, Panos Deloukas, Christian Gieger, Henrik Grönberg, Per Hall, Andrew T Hattersley, Christian Hengstenberg, Wolfgang Hoffman, G Mark Lathrop, Veikko Salomaa, Stefan Schreiber, Manuela Uda, Dawn Waterworth, Alan F Wright, Themistocles L Assimes, Inês Barroso, Albert Hofman, Karen L Mohlke, Dorret I Boomsma, Mark J Caulfield, L Adrienne Cupples, Jeanette Erdmann, Caroline S Fox, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Richard B Hayes, Marjo-Riitta Järvelin, Vincent Mooser, Patricia B Munroe, Willem H Ouwehand, Brenda W Penninx, Peter P Pramstaller, Thomas Quertermous, Igor Rudan, Nilesh J Samani, Timothy D Spector, Henry Völzke, Hugh Watkins, James F Wilson, Leif C Groop, Talin Haritunians, Frank B Hu, Robert C Kaplan, Andres Metspalu, Kari E North, David Schlessinger, Nicholas J Wareham, David J Hunter, Jeffrey R O'Connell, David P Strachan, H-Erich Wichmann, Ingrid B Borecki, Cornelia M van Duijn, Eric E Schadt, Unnur Thorsteinsdottir, Leena Peltonen, André G Uitterlinden, Peter M Visscher, Nilanjan Chatterjee, Ruth J F Loos, Michael Boehnke, Mark I McCarthy, Erik Ingelsson, Cecilia M Lindgren, Gonçalo R Abecasis, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn.
Nature
PUBLISHED: 04-23-2010
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Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?
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Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.
Diabetes
PUBLISHED: 02-25-2010
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OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
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Multiobjective evolutionary optimisation for surface-enhanced Raman scattering.
Anal Bioanal Chem
PUBLISHED: 01-21-2010
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In most optimisation experiments, a single parameter is first optimised before a second and then third one are subsequently modified to give the best result. By contrast, we believe that simultaneous multiobjective optimisation is more powerful; therefore, an optimisation of the experimental conditions for the colloidal SERS detection of L-cysteine was carried out. Six aggregating agents and three different colloids (citrate, borohydride and hydroxylamine reduced silver) were tested over a wide range of concentrations for the enhancement and the reproducibility of the spectra produced. The optimisation was carried out using two methods, a full factorial design (FF, a standard method from the experimental design literature) and, for the first time, a multiobjective evolutionary algorithm (MOEA), a method more usually applied to optimisation problems in computer science. Simulation results suggest that the evolutionary approach significantly out-performs random sampling. Real experiments applying the evolutionary method to the SERS optimisation problem led to a 32% improvement in enhancement and reproducibility compared with the FF method, using far fewer evaluations.
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Quantitative assessment of moisture damage for cacao bean quality using two-dimensional gas chromatography combined with time-of-flight mass spectrometry and chemometrics.
J Chromatogr A
PUBLISHED: 01-19-2010
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Quality control of cacao beans is a significant issue in the chocolate industry. In this report, we describe how moisture damage to cacao beans alters the volatile chemical signature of the beans in a way that can be tracked quantitatively over time. The chemical signature of the beans is monitored via sampling the headspace of the vapor above a given bean sample. Headspace vapor sampled with solid-phase micro-extraction (SPME) was detected and analyzed with comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GCxGC-TOFMS). Cacao beans from six geographical origins (Costa Rica, Ghana, Ivory Coast, Venezuela, Ecuador, and Panama) were analyzed. Twenty-nine analytes that change in concentration levels via the time-dependent moisture damage process were measured using chemometric software. Biomarker analytes that were independent of geographical origin were found. Furthermore, prediction algorithms were used to demonstrate that moisture damage could be verified before there were visible signs of mold by analyzing subsets of the 29 analytes. Thus, a quantitative approach to quality screening related to the identification of moisture damage in the absence of visible mold is presented.
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Analysis of a complete DNA-protein affinity landscape.
J R Soc Interface
PUBLISHED: 07-22-2009
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Properties of biological fitness landscapes are of interest to a wide sector of the life sciences, from ecology to genetics to synthetic biology. For biomolecular fitness landscapes, the information we currently possess comes primarily from two sources: sparse samples obtained from directed evolution experiments; and more fine-grained but less authentic information from in silico models (such as NK-landscapes). Here we present the entire protein-binding profile of all variants of a nucleic acid oligomer 10 bases in length, which we have obtained experimentally by a series of highly parallel on-chip assays. The resulting complete landscape of sequence-binding pairs, comprising more than one million binding measurements in duplicate, has been analysed statistically using a number of metrics commonly applied to synthetic landscapes. These metrics show that the landscape is rugged, with many local optima, and that this arises from a combination of experimental variation and the natural structural properties of the oligonucleotides.
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Development and performance of a gas chromatography-time-of-flight mass spectrometry analysis for large-scale nontargeted metabolomic studies of human serum.
Anal. Chem.
PUBLISHED: 07-18-2009
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A method for the preparation and GC-TOF-MS analysis of human serum samples has been developed and evaluated for application in long-term metabolomic studies. Serum samples were deproteinized using 3:1 methanol/serum, dried in a vacuum concentrator, and chemically derivatized in a two-stage process. Samples were analyzed by GC-TOF-MS with a 25 min analysis time. In addition, quality control (QC) samples were used to quantify process variability. Optimization of chemical derivatization was performed. Products were found to be stable for 30 h after derivatization. An assessment of within-day repeatability and within-week reproducibility demonstrates that excellent performance is observed with our developed method. Analyses were consistent over a 5 month period. Additional method testing, using spiked serum samples, showed the ability to define metabolite differences between samples from a population and samples spiked with metabolites standards. This methodology allows the continuous acquisition and application of data acquired over many months in long-term metabolomic studies, including the HUSERMET project (http://www.husermet.org/).
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Characterizing the admixed African ancestry of African Americans.
Genome Biol.
PUBLISHED: 05-27-2009
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Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.
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In silico modelling of directed evolution: Implications for experimental design and stepwise evolution.
J. Theor. Biol.
PUBLISHED: 05-15-2009
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We model the process of directed evolution (DE) in silico using genetic algorithms. Making use of the NK fitness landscape model, we analyse the effects of mutation rate, crossover and selection pressure on the performance of DE. A range of values of K, the epistatic interaction of the landscape, are considered, and high- and low-throughput modes of evolution are compared. Our findings suggest that for runs of or around ten generations duration-as is typical in DE-there is little difference between the way in which DE needs to be configured in the high- and low-throughput regimes, nor across different degrees of landscape epistasis. In all cases, a high selection pressure (but not an extreme one) combined with a moderately high mutation rate works best, while crossover provides some benefit but only on the less rugged landscapes. These genetic algorithms were also compared with a "model-based approach" from the literature, which uses sequential fixing of the problem parameters based on fitting a linear model. Overall, we find that purely evolutionary techniques fare better than do model-based approaches across all but the smoothest landscapes.
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Artefacts and biases affecting the evaluation of scoring functions on decoy sets for protein structure prediction.
Bioinformatics
PUBLISHED: 03-17-2009
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Decoy datasets, consisting of a solved protein structure and numerous alternative native-like structures, are in common use for the evaluation of scoring functions in protein structure prediction. Several pitfalls with the use of these datasets have been identified in the literature, as well as useful guidelines for generating more effective decoy datasets. We contribute to this ongoing discussion an empirical assessment of several decoy datasets commonly used in experimental studies.
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Array-based evolution of DNA aptamers allows modelling of an explicit sequence-fitness landscape.
Nucleic Acids Res.
PUBLISHED: 02-04-2009
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Mapping the landscape of possible macromolecular polymer sequences to their fitness in performing biological functions is a challenge across the biosciences. A paradigm is the case of aptamers, nucleic acids that can be selected to bind particular target molecules. We have characterized the sequence-fitness landscape for aptamers binding allophycocyanin (APC) protein via a novel Closed Loop Aptameric Directed Evolution (CLADE) approach. In contrast to the conventional SELEX methodology, selection and mutation of aptamer sequences was carried out in silico, with explicit fitness assays for 44,131 aptamers of known sequence using DNA microarrays in vitro. We capture the landscape using a predictive machine learning model linking sequence features and function and validate this model using 5500 entirely separate test sequences, which give a very high observed versus predicted correlation of 0.87. This approach reveals a complex sequence-fitness mapping, and hypotheses for the physical basis of aptameric binding; it also enables rapid design of novel aptamers with desired binding properties. We demonstrate an extension to the approach by incorporating prior knowledge into CLADE, resulting in some of the tightest binding sequences.
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Development of a robust and repeatable UPLC-MS method for the long-term metabolomic study of human serum.
Anal. Chem.
PUBLISHED: 01-28-2009
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A method for performing untargeted metabolomic analysis of human serum has been developed based on protein precipitation followed by Ultra Performance Liquid Chromatography and Time-of-Flight mass spectrometry (UPLC-TOF-MS). This method was specifically designed to fulfill the requirements of a long-term metabolomic study, spanning more than 3 years, and it was subsequently thoroughly evaluated for robustness and repeatability. We describe here the observed drift in instrumental performance over time and its improvement with adjustment of the length of analytical block. The optimal setup for our purpose was further validated against a set of serum samples from 30 healthy individuals. We also assessed the reproducibility of chromatographic columns with the same chemistry of stationary phase from the same manufacturer but from different production batches. The results have allowed the authors to prepare SOPs for "fit for purpose" long-term UPLC-MS metabolomic studies, such as are being employed in the HUSERMET project. This method allows the acquisition of data and subsequent comparison of data collected across many months or years.
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Aptamer evolution for array-based diagnostics.
Anal. Biochem.
PUBLISHED: 01-27-2009
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Closed loop aptameric directed evolution, (CLADE) is a technique enabling simultaneous discovery, evolution, and optimization of aptamers. It was previously demonstrated using a fluorescent protein, and here we extend its applicability with the generation of surface-bound aptamers for targets containing no natural fluorescence. Starting from a random population, in four generations CLADE produced a new aptamer to thrombin with high specificity and affinity. The best aptameric sequence was void of the set of four guanine repeats typifying thrombin aptamers and, thus, highlights the benefits of evolution performed in an environment closely mimicking the final diagnostic application.
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Analysis of aptamer sequence activity relationships.
Integr Biol (Camb)
PUBLISHED: 01-01-2009
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DNA sequences that can bind selectively and specifically to target molecules are known as aptamers. Normally such binding analyses are performed using soluble aptamers. However, there is much to be gained by using an on-chip or microarray format, where a large number of aptameric DNA sequences can be interrogated simultaneously. To calibrate the system, known thrombin binding aptamers (TBAs) have been mutated systematically, producing large populations that allow exploration of key structural aspects of the overall binding motif. The ability to discriminate between background noise and low affinity binding aptamers can be problematic on arrays, and we use the mutated sequences to establish appropriate experimental conditions and their limitations for two commonly used fluorescence-based detection methods. Having optimized experimental conditions, high-density oligonucleotide microarrays were used to explore the entire loop-sequence-functionality relationship creating a detailed model based on over 40 000 analyses, describing key features for quadruplex-forming sequences.
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Large-scale association analysis identifies new risk loci for coronary artery disease.
, Panos Deloukas, Stavroula Kanoni, Christina Willenborg, Martin Farrall, Themistocles L Assimes, John R Thompson, Erik Ingelsson, Danish Saleheen, Jeanette Erdmann, Benjamin A Goldstein, Kathleen Stirrups, Inke R König, Jean-Baptiste Cazier, Asa Johansson, Alistair S Hall, Jong-Young Lee, Cristen J Willer, John C Chambers, Tonu Esko, Lasse Folkersen, Anuj Goel, Elin Grundberg, Aki S Havulinna, Weang K Ho, Jemma C Hopewell, Niclas Eriksson, Marcus E Kleber, Kati Kristiansson, Per Lundmark, Leo-Pekka Lyytikäinen, Suzanne Rafelt, Dmitry Shungin, Rona J Strawbridge, Gudmar Thorleifsson, Emmi Tikkanen, Natalie Van Zuydam, Benjamin F Voight, Lindsay L Waite, Weihua Zhang, Andreas Ziegler, Devin Absher, David Altshuler, Anthony J Balmforth, Inês Barroso, Peter S Braund, Christof Burgdorf, Simone Claudi-Boehm, David Cox, Maria Dimitriou, Ron Do, Alex S F Doney, NourEddine El Mokhtari, Per Eriksson, Krista Fischer, Pierre Fontanillas, Anders Franco-Cereceda, Bruna Gigante, Leif Groop, Stefan Gustafsson, Jörg Hager, Göran Hallmans, Bok-Ghee Han, Sarah E Hunt, Hyun M Kang, Thomas Illig, Thorsten Kessler, Joshua W Knowles, Genovefa Kolovou, Johanna Kuusisto, Claudia Langenberg, Cordelia Langford, Karin Leander, Marja-Liisa Lokki, Anders Lundmark, Mark I McCarthy, Christa Meisinger, Olle Melander, Evelin Mihailov, Seraya Maouche, Andrew D Morris, Martina Müller-Nurasyid, Kjell Nikus, John F Peden, N William Rayner, Asif Rasheed, Silke Rosinger, Diana Rubin, Moritz P Rumpf, Arne Schäfer, Mohan Sivananthan, Ci Song, Alexandre F R Stewart, Sian-Tsung Tan, Gudmundur Thorgeirsson, C Ellen van der Schoot, Peter J Wagner, George A Wells, Philipp S Wild, Tsun-Po Yang, Philippe Amouyel, Dominique Arveiler, Hanneke Basart, Michael Boehnke, Eric Boerwinkle, Paolo Brambilla, Francois Cambien, Adrienne L Cupples, Ulf de Faire, Abbas Dehghan, Patrick Diemert, Stephen E Epstein, Alun Evans, Marco M Ferrario, Jean Ferrières, Dominique Gauguier, Alan S Go, Alison H Goodall, Villi Gudnason, Stanley L Hazen, Hilma Holm, Carlos Iribarren, Yangsoo Jang, Mika Kähönen, Frank Kee, Hyo-Soo Kim, Norman Klopp, Wolfgang Koenig, Wolfgang Kratzer, Kari Kuulasmaa, Markku Laakso, Reijo Laaksonen, Ji-Young Lee, Lars Lind, Willem H Ouwehand, Sarah Parish, Jeong E Park, Nancy L Pedersen, Annette Peters, Thomas Quertermous, Daniel J Rader, Veikko Salomaa, Eric Schadt, Svati H Shah, Juha Sinisalo, Klaus Stark, Kari Stefansson, David-Alexandre Trégouët, Jarmo Virtamo, Lars Wallentin, Nicholas Wareham, Martina E Zimmermann, Markku S Nieminen, Christian Hengstenberg, Manjinder S Sandhu, Tomi Pastinen, Ann-Christine Syvänen, G Kees Hovingh, George Dedoussis, Paul W Franks, Terho Lehtimäki, Andres Metspalu, Pierre A Zalloua, Agneta Siegbahn, Stefan Schreiber, Samuli Ripatti, Stefan S Blankenberg, Markus Perola, Robert Clarke, Bernhard O Boehm, Christopher O'Donnell, Muredach P Reilly, Winfried März, Rory Collins, Sekar Kathiresan, Anders Hamsten, Jaspal S Kooner, Unnur Thorsteinsdottir, John Danesh, Colin N A Palmer, Robert Roberts, Hugh Watkins, Heribert Schunkert, Nilesh J Samani.
Nat. Genet.
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Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
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Exploiting genomic knowledge in optimising molecular breeding programmes: algorithms from evolutionary computing.
PLoS ONE
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Comparatively few studies have addressed directly the question of quantifying the benefits to be had from using molecular genetic markers in experimental breeding programmes (e.g. for improved crops and livestock), nor the question of which organisms should be mated with each other to best effect. We argue that this requires in silico modelling, an approach for which there is a large literature in the field of evolutionary computation (EC), but which has not really been applied in this way to experimental breeding programmes. EC seeks to optimise measurable outcomes (phenotypic fitnesses) by optimising in silico the mutation, recombination and selection regimes that are used. We review some of the approaches from EC, and compare experimentally, using a biologically relevant in silico landscape, some algorithms that have knowledge of where they are in the (genotypic) search space (G-algorithms) with some (albeit well-tuned ones) that do not (F-algorithms). For the present kinds of landscapes, F- and G-algorithms were broadly comparable in quality and effectiveness, although we recognise that the G-algorithms were not equipped with any prior knowledge of epistatic pathway interactions. This use of algorithms based on machine learning has important implications for the optimisation of experimental breeding programmes in the post-genomic era when we shall potentially have access to the full genome sequence of every organism in a breeding population. The non-proprietary code that we have used is made freely available (via Supplementary information).
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Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp.
Metab. Clin. Exp.
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Two direct measurements of peripheral insulin sensitivity are the M value derived from the euglycemic, hyperinsulinemic clamp (EC) and the steady-state plasma glucose (SSPG) concentration derived from the insulin suppression test (IST). Prior work suggests that these measures are highly correlated, but the agreement between them is unknown. To determine the agreement between SSPG and M and to develop transformation equations to convert SSPG to M and vice versa, we directly compared these two measurements in the same individuals.
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Exploring predisposition and treatment response--the promise of genomics.
Prog Cardiovasc Dis
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Spurred by large-scale public and private efforts as well as technological developments, the last few years have seen a major leap forward in our understanding of the genetic basis of cardiovascular disease. This revolution is in its infancy and will continue to alter the medical landscape for years to come. There is a need within the general cardiology community to develop a better understanding about how these developments may alter routine clinical care. In this review, we will provide an overview of the current state of genetics as pertains to rare cardiovascular diseases and then review advances in the discovery of the genetic basis of common disease with the potential for improved risk assessment and drug development. We will also outline a few recent examples of pharmacogenetic advances that are already starting to become a part of clinical management and finally discuss the promise as well as the challenges in using next-generation sequencing technologies to provide personalized cardiovascular care.
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Use and overuse of left ventriculography.
Am. Heart J.
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Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.