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GST Primary GST Primary Best Strategies for Health Care Quality Im... Best Strategies for Health Care Quality Improvement - Diabetes Quality Improvement Strategies for Antibio... Kathryn McDonald, Stanford-UCSF Evidence-b... Systematic review assessing the effect of ... Quality Improvement Strategies for Antibiotics Management Kathryn McDonald, Stanford-UCSF Evidence-based Practice Center, 117 Encina Commons, Stanford, CA 94305-6019, Kathy.mcdonald@stanford.edu Systematic review assessing the effect of quality improvement strategies on appropriate prescribing of antibiotics and appropriate choice of antibiotics. Adherence Adherence Assistive Devices Assistive Devices Childhood Burn Hanson MacMillan Childhood Burn Hanson MacMillan CLSA_9 CLSA_9 Cyberabuse Cyberabuse Cognitive Behavioural Therapy for Violent ... This review included randomized trials abo... Cognitive Behavioural Therapy for Violent Men who Batter Their Partners This review included randomized trials about the effects of cognitive behavioral therapy on domestic violence. The intervention included programs based on the Duluth Model. The violence had to be committed by a male toward his female partner. The violence also had to be physical. The primary outcomes were new arrests and convictions, and new reports of violence. CABG vs PCI CABG vs PCI Quality Improvement Strategies for Prevent... Quality Improvement Strategies for Preventing Nosocomial Infections (Created 17-Feb-06) Quality Improvement Strategies for Asthma ... Quality Improvement Strategies for Asthma Control Erectile Dysfunction (Created 30-Jan-06) Erectile Dysfunction (Created 30-Jan-06) Inequality - Smoking Cessation to Reduce S... This review was the first part of a projec... Inequality - Smoking Cessation to Reduce Socio-Economic Differences This review was the first part of a project about inequality. It included randomized trials about the effect of smoking cessation interventions on reducing socio-economic differences. The studies had to report data either on persons with low socio-economic groups status or, preferably, on both low and high socio-economic groups. Diet and Physical Activity to Reduce Socio... This review was the second part in a proje... Diet and Physical Activity to Reduce Socio-Economic Differences This review was the second part in a project about inequality. It included randomized trials about the effect of interventions on reducing socio-economic differences in diet and physical activity. The studies had to report data either on persons with low socio-economic groups status or, preferably, on both low and high socio-economic groups. Workfare The data in SRS are not identical to the d... Workfare The data in SRS are not identical to the data in the published report. We used SRS only for an updated search. The review included randomized trials about the effect of welfare-to-work programs. Participants were welfare recipients. There were basically two types of programs. The educational type tried to build knowledge and skills in order to help the welfare recipients acquire jobs that could support them economically. The "work first" approach was more aimed at getting the participants quickly into a job. Exercise interventions for the management ... The objective of this systematic review wa... Exercise interventions for the management of frailty The objective of this systematic review was to examine the effectiveness of current exercise interventions on the management of frailty. A comprehensive search of Medline, Embase, Psycinfo, Cinahl, Scopus, Ageline, Eric, and SportDiscus databases was conducted and produced 1808 citations. So far we have completed 2 levels of “title and abstract” screening and we ended up with 262 articles. We have just started the full text screening. Eligibility criteria included original studies whose participants were identified as frail or prefrail with specific criteria and in which structured physical activity was included as at least one component of the intervention. Create a free account, build a dictionary with saved terms to re-use later! Public Domestic Violence - Using Cognitive Behavior Therapy Smoking Cessation to Reduce Socio-Economic Differences Diet and Physical Activity to Reduce Socio-Economic Differences Workfare Exercise Interventions for the Management of Frailty Search     Simple Advanced Refine (3 coded questions)  Any of these:   Exact Phrase: All of these: None of these: Author: Periodical: Projects: No restrictions   Libraries: Public   Select SRS Projects Show Saved Terms Select Library Show articles that do not have abstracts  Humans or Animals Humans Animals Type of Article Clinical Trial Editorial Letter Meta-Analysis Practice Guideline Randomized Controlled Trial Review Addresses Bibliography Biography Case Reports Classical Article Clinical Conference Clinical Trial, Phase I Clinical Trial, Phase II Clinical Trial, Phase III Clinical Trial, Phase IV Comment Comparative Study Consensus Development Conference Consensus Development Conference, NIH Controlled Clinical Trial Corrected and Republished Article Dictionary Directory Duplicate Publication English Abstract Evaluation Studies Festschrift Government Publications Guideline Historical Article Interview In Vitro Journal Article Lectures Legal Cases Legislation Multicenter Study News Newspaper Article Overall Patient Education Handout Periodical Index Published Erratum Retracted Publication Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 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Retraction of Publication Scientific Integrity Review Support of Research Technical Report Twin Study Validation Studies Not a Primary Study or Review Unknown Primary Study Case Series Case Control Cohort Study Observational Study Qualitative Research CBA or ITS Registry Double Blind Controlled before after study Quasi-randomized trial Simple before after study Cluster-RCT Non-Randomized Study Report Book Book chapter Dissertation Conference procedings Secondary Research Not RCT Ages All Infant: birth-23 months All Child: 0-18 years All Adult: 19+ years Newborn: birth-1 month Infant: 1-23 months Preschool Child: 2-5 years Child: 6-12 years Adolescent: 13-18 years Adult: 19-44 years Middle Aged: 45-64 years Middle Aged + Aged: 45+ years Aged: 65+ years 80 and over: 80+ years Undetermined Results(1-25 of 161) Sort By: Publication Date Relevance Took: 0.112 seconds to search 17,750,454  Action: Copy Results to new Clipboard Build Search Link Page 1 of 7 1 2 3 4 > Last >> (161 articles found) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nov 2007 Wellcome Trust Case Control Consortium ,Australo-Anglo-American Spondylitis Consortium (TASC) ,Paul R Burton,David G Clayton,Lon R Cardon,Nick Craddock,Panos Deloukas,Audrey Duncanson,Dominic P Kwiatkowski,Mark I McCarthy,Willem H Ouwehand,Nilesh J Samani,John A Todd,Peter Donnelly,Jeffrey C Barrett,Dan Davison,Doug Easton,David M Evans,Hin-Tak Leung,Jonathan L Marchini,Andrew P Morris,Chris C A Spencer,Martin D Tobin,Antony P Attwood,James P Boorman,Barbara Cant,Ursula Everson,Judith M Hussey,Jennifer D Jolley,Alexandra S Knight,Kerstin Koch,Elizabeth Meech,Sarah Nutland,Christopher V Prowse,Helen E Stevens,Niall C Taylor,Graham R Walters,Neil M Walker,Nicholas A Watkins,Thilo Winzer,Richard W Jones,Wendy L McArdle,Susan M Ring,David P Strachan,Marcus Pembrey,Gerome Breen,David St Clair,Sian Caesar,Katharine Gordon-Smith,Lisa Jones,Christine Fraser,Elaine K Green,Detelina Grozeva,Marian L Hamshere,Peter A Holmans,Ian R Jones,George Kirov,Valentina Moskivina,Ivan Nikolov,Michael C O'Donovan,Michael J Owen,David A Collier,Amanda Elkin,Anne Farmer,Richard Williamson,Peter McGuffin,Allan H Young,I Nicol Ferrier,Stephen G Ball,Anthony J Balmforth,Jennifer H Barrett,Timothy D Bishop,Mark M Iles,Azhar Maqbool,Nadira Yuldasheva,Alistair S Hall,Peter S Braund,Richard J Dixon,Massimo Mangino,Suzanne Stevens,John R Thompson,Francesca Bredin,Mark Tremelling,Miles Parkes,Hazel Drummond,Charles W Lees,Elaine R Nimmo,Jack Satsangi,Sheila A Fisher,Alastair Forbes,Cathryn M Lewis,Clive M Onnie,Natalie J Prescott,Jeremy Sanderson,Christopher G Matthew,Jamie Barbour,M Khalid Mohiuddin,Catherine E Todhunter,John C Mansfield,Tariq Ahmad,Fraser R Cummings,Derek P Jewell,John Webster,Morris J Brown,Mark G Lathrop,John Connell,Anna Dominiczak,Carolina A Braga Marcano,Beverley Burke,Richard Dobson,Johannie Gungadoo,Kate L Lee,Patricia B Munroe,Stephen J Newhouse,Abiodun Onipinla,Chris Wallace,Mingzhan Xue,Mark Caulfield,Martin Farrall,Anne Barton,Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee ,Ian N Bruce,Hannah Donovan,Steve Eyre,Paul D Gilbert,Samantha L Hilder,Anne M Hinks,Sally L John,Catherine Potter,Alan J Silman,Deborah P M Symmons,Wendy Thomson,Jane Worthington,David B Dunger,Barry Widmer,Timothy M Frayling,Rachel M Freathy,Hana Lango,John R B Perry,Beverley M Shields,Michael N Weedon,Andrew T Hattersley,Graham A Hitman,Mark Walker,Kate S Elliott,Christopher J Groves,Cecilia M Lindgren,Nigel W Rayner,Nicolas J Timpson,Eleftheria Zeggini,Melanie Newport,Giorgio Sirugo,Emily Lyons,Fredrik Vannberg,Adrian V S Hill,Linda A Bradbury,Claire Farrar,Jennifer J Pointon,Paul Wordsworth,Matthew A Brown,Jayne A Franklyn,Joanne M Heward,Matthew J Simmonds,Stephen C L Gough,Sheila Seal,Breast Cancer Susceptibility Collaboration (UK) ,Michael R Stratton,Nazneen Rahman,Maria Ban,An Goris,Stephen J Sawcer,Alastair Compston,David Conway,Muminatou Jallow,Melanie Newport,Giorgio Sirugo,Kirk A Rockett,Suzannah J Bumpstead,Amy Chaney,Kate Downes,Mohammed J R Ghori,Rhian Gwilliam,Sarah E Hunt,Michael Inouye,Andrew Keniry,Emma King,Ralph McGinnis,Simon Potter,Rathi Ravindrarajah,Pamela Whittaker,Claire Widden,David Withers,Niall J Cardin,Dan Davison,Teresa Ferreira,Joanne Pereira-Gale,Ingeleif B Hallgrimsdo'ttir,Bryan N Howie,Zhan Su,Yik Ying Teo,Damjan Vukcevic,David Bentley,Matthew A Brown,Alastair Compston,Martin Farrall,Alistair S Hall,Andrew T Hattersley,Adrian V S Hill,Miles Parkes,Marcus Pembrey,Michael R Stratton,Sarah L Mitchell,Paul R Newby,Oliver J Brand,Jackie Carr-Smith,Simon H S Pearce,R McGinnis,A Keniry,P Deloukas,John D Reveille,Xiaodong Zhou,Anne-Marie Sims,Alison Dowling,Jacqueline Taylor,Tracy Doan,John C Davis,Laurie Savage,Michael M Ward,Thomas L Learch,Michael H Weisman,Mathew Brown We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control ... ( view more )dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Two unusual cases of first trimester prenatal diagnosis of cystic fibrosis using DNA probes. Mar 1987 H Y Law,P Stanier,R Williamson,B Modell,R H Ward,M Petrou,J Old,M Farrall There are now several DNA probes which localize the cystic fibrosis mutation (CF) to chromosome 7q2.2-q3.1. The most tightly linked probes, pJ3.11 and met, are useful for first trimester prenatal diagnosis for many families provided that there is at least one living child affected by CF (Farrall et... ( view more ) al., 1986). We describe here two families seeking prenatal diagnosis for CF which present unusual counselling problems. The first is an extended family in which there is no living affected member with CF; the second, a consanguinous marriage at risk both for cystic fibrosis and beta-thalassaemia. In both cases first trimester chorionic villus sampling and DNA haplotype analysis predicted that the fetus is a carrier for CF, and in the doubly affected family a carrier for beta-thalassaemia as well. Both pregnancies resulted in live births and subsequent immunoreactive trypsin estimations were both in the normal range. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Further data supporting linkage between cystic fibrosis and the met oncogene and haplotype analysis with met and pJ3.11. Dec 1986 M Farrall,E Watson,G Bates,G Bell,J Bell,K A Davies,X Estivill,H Kruyer,H Y Law,N Lench The linkage of cystic fibrosis (CF) and the polymorphic DNA markers pJ3.11, met, 7C22, DOCR1-917, COL1A2, and TCRB have jointly localized the mutation causing CF to chromosome 7q2.1-3.1. We report further linkage data with two polymorphic markers at the met oncogene locus, pmetH and pmetD, which su... ( view more )pports the tight linkage found by White et al. between CF and met. One family shows evidence for meiotic recombination between CF and met. Analysis of haplotypes in CF pedigrees collected for linkage studies combined with data from single affected families requesting prenatal diagnosis (Farrall et al., Lancet i:1402-1404, 1986) shows CF and met to be in linkage equilibrium in our population while pJ3.11-CF haplotypes show a deviation from the equilibrium frequencies. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The bHLH/Per-Arnt-Sim transcription factor SIM2 regulates muscle transcript myomesin2 via a novel, non-canonical E-box sequence. Jun 2008 Susan Woods,Alexandra Farrall,Carl Procko,Murray L Whitelaw Despite a growing number of descriptive studies that show Single-minded 2 (Sim2) is not only essential for murine survival, but also upregulated in colon, prostate and pancreatic tumours, there is a lack of direct target genes identified for this basic helix-loop-helix/PAS transcription factor. We ... ( view more )have performed a set of microarray experiments aimed at identifying genes that are differentially regulated by SIM2, and successfully verified that the Myomesin2 (Myom2) gene is SIM2-responsive. Although SIM2 has been reported to be a transcription repressor, we find that SIM2 induces transcription of Myom2 and activates the Myom2 promoter sequence when co-expressed with the heterodimeric partner protein, ARNT1, in human embryonic kidney cells. Truncation and mutation of the Myom2 promoter sequence, combined with chromatin immunoprecipitation studies in cells, has lead to the delineation of a non-canonical E-box sequence 5'-AACGTG-3' that is bound by SIM2/ARNT1 heterodimers. Interestingly, in immortalized human myoblasts knock down of Sim2 results in increased levels of Myom2 RNA, suggesting that SIM2 is acting as a repressor in these cells and so its activity is likely to be highly context dependent. This is the first report of a direct SIM2/ARNT1 target gene with accompanying analysis of a functional response element. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Genome-wide association analysis identifies 20 loci that influence adult height. May 2008 Michael N Weedon,Hana Lango,Cecilia M Lindgren,Chris Wallace,David M Evans,Massimo Mangino,Rachel M Freathy,John R B Perry,Suzanne Stevens,Alistair S Hall,Nilesh J Samani,Beverly Shields,Inga Prokopenko,Martin Farrall,Anna Dominiczak,Diabetes Genetics Initiative ,Wellcome Trust Case Control Consortium ,Toby Johnson,Sven Bergmann,Jacques S Beckmann,Peter Vollenweider,Dawn M Waterworth,Vincent Mooser,Colin N A Palmer,Andrew D Morris,Willem H Ouwehand,Cambridge GEM Consortium ,Jing Hua Zhao,Shengxu Li,Ruth J F Loos,Inês Barroso,Panagiotis Deloukas,Manjinder S Sandhu,Eleanor Wheeler,Nicole Soranzo,Michael Inouye,Nicholas J Wareham,Mark Caulfield,Patricia B Munroe,Andrew T Hattersley,Mark I McCarthy,Timothy M Frayling Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional ... ( view more )16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Changes in background blood-brain barrier integrity between lacunar and cortical ischemic stroke subtypes. Apr 2008 Joanna M Wardlaw,Andrew Farrall,Paul A Armitage,Trevor Carpenter,Francesca Chappell,Fergus Doubal,Debashish Chowdhury,Vera Cvoro,Martin S Dennis BACKGROUND AND PURPOSE: Lacunar stroke is associated with endothelial dysfunction and histologically with intrinsic cerebral microvascular disease of unknown cause. Endothelial dysfunction could impair blood-brain barrier integrity. We assessed background blood-brain barrier leakage in patients wit... ( view more )h lacunar ischemic stroke compared with cortical stroke controls. METHODS: We recruited patients with lacunar or mild cortical ischemic stroke and assessed generalized cerebral blood-brain barrier leak with MRI and intravenous gadolinium at least 1 month after stroke. We used detailed image processing to compare signal change before and for 30 minutes postcontrast throughout gray matter, white matter, and cerebrospinal fluid with summary analyses and general linear modeling. RESULTS: Among 48 patients (29 lacunar, 19 cortical), postcontrast enhancement was significantly higher in cerebrospinal fluid (P=0.04, Mann-Whitney U), and nonsignificantly higher in white matter, in lacunar than in cortical strokes, with no difference in gray matter. General linear modeling confirmed significantly greater postcontrast enhancement in cerebrospinal fluid in lacunar patients than in cortical controls (t=3.37, P<0.0008). CONCLUSIONS: These preliminary data suggest that the blood-brain barrier may be dysfunctional throughout subcortical white matter (white matter drains via interstitial spaces to cerebrospinal fluid) in patients with lacunar stroke. Further studies are required to confirm these findings and determine whether abnormal blood-brain barrier might predate development of lacunar disease. Blood-brain barrier dysfunction may be an important mechanism for brain damage in cerebral microvascular disease. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Mar 15, 2008 Helen M Broadbent,John F Peden,Stefan Lorkowski,Anuj Goel,Halit Ongen,Fiona Green,Robert Clarke,Rory Collins,Maria Grazia Franzosi,Gianni Tognoni,Udo Seedorf,Stephan Rust,Per Eriksson,Anders Hamsten,Martin Farrall,Hugh Watkins,PROCARDIS consortium Genome-wide association studies have identified a region on chromosome 9p that is associated with coronary artery disease (CAD). The region is also associated with type 2 diabetes (T2D), a risk factor for CAD, although different SNPs were reported to be associated to each disease in separate studie... ( view more )s. We have undertaken a case-control study in 4251 CAD cases and 4443 controls in four European populations using previously reported ('literature') and tagging SNPs. We replicated the literature SNPs (P = 8x10(-13); OR = 1.29; 95% CI: 1.20-1.38) and showed that the strong consistent association detected by these SNPs is a consequence of a 'yin-yang' haplotype pattern spanning 53 kb. There was no evidence of additional CAD susceptibility alleles over the major risk haplotype. CAD patients without myocardial infarction (MI) showed a trend towards stronger association than MI patients. The CAD susceptibility conferred by this locus did not differ by sex, age, smoking, obesity, hypertension or diabetes. A simultaneous test of CAD and diabetes susceptibility with CAD and T2D-associated SNPs indicated that these associations were independent of each other. Moreover, this region was not associated with differences in plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fibrinogen, albumin, uric acid, bilirubin or homocysteine, although the CAD-high-risk allele was paradoxically associated with lower triglyceride levels. A large antisense non-coding RNA gene (ANRIL) collocates with the high-risk haplotype, is expressed in tissues and cell types that are affected by atherosclerosis and is a prime candidate gene for the chromosome 9p CAD locus. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Genome-wide linkage analysis of electrocardiographic and echocardiographic left ventricular hypertrophy in families with hypertension. Feb 2008 Bongani M Mayosi,Peter J Avery,Martin Farrall,Bernard Keavney,Hugh Watkins AIMS: To localize chromosomal regions (or quantitative trait loci) that harbour genetic variants influencing the variability of electrocardiographic (ECG) and echocardiographic left ventricular hypertrophy (LVH). METHODS AND RESULTS: We evaluated genetic linkage to ECG Sokolow-Lyon voltage, ECG Cor... ( view more )nell voltage product, ECG left ventricular (LV) mass, and to echocardiographic septal wall thickness, LV cavity size, and LV mass in 868 members of 224 white British families. A genome-wide scan was performed with microsatellite markers that covered the genome at 10-cM intervals and linkage was assessed by variance components analysis. We identified chromosomal regions suggestive of linkage for Sokolow-Lyon voltage on chromosome 10q23.1 [log(10) of the odds (LOD = 2.21, P = 0.0007)], for ECG Cornell voltage product on chromosome 17p13.3 (LOD = 2.67; P = 0.0002), and for ECG LV mass on chromosome 12q14.1 (LOD = 2.19; P = 0.0007). There was a single region of possible linkage for echocardiographic LV mass on chromosome 5p14.1 (LOD = 1.6; P = 0.003). CONCLUSION: Stronger genetic signals for LVH were found using electrocardiographic than echocardiographic measurements, and the genetic determinants of each of these appear to be distinct. Chromosomes 10, 12, and 17 are likely to harbour genetic loci that exert a major influence on electrocardiographic LVH. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Quantitative trait genetic linkage analysis of body mass index in familial coronary artery disease. 2008 Claudia Specchia,Simona Barlera,Benedetta D Chiodini,Enrico B Nicolis,Martin Farrall,John Peden,Rory Collins,Hugh Watkins,Gianni Tognoni,Maria Grazia Franzosi,PROCARDIS Consortium OBJECTIVE: Body mass index (BMI) is one of the most reproducible and commonly used proxies for obesity and is known to be influenced by many environmental causes as well as genetic factors. Identification of susceptibility genes for BMI regulation has been difficult. Reasons for these inconclusive ... ( view more )results are both methodological and related to obesity aetiology. A genome-wide linkage analysis was performed to localise Quantitative trait loci influencing BMI in a large cohort collected in the PROCARDIS coronary heart disease study consisting of 1,812 informative families. Methods: Multipoint linkage analysis for BMI was conducted using both a variance component approach and a model-free regression method, and the resulting LOD scores were compared. RESULTS: The strongest evidence for linkage was detected on chromosomes 13 (LOD 1.6). Other regions showing a LOD score greater than 1 were observed on chromosomes 3, 5, 11, 12 and 15. These results were mainly confirmed by the three different approaches used in the analysis. CONCLUSION: Our study did not find any locus with strongly supporting evidence for linkage to BMI even in such a large sample. Our results confirm the substantial genetic heterogeneity influencing BMI regulation that has emerged from the majority of genome scans so far published. Copyright (c) 2008 S. Karger AG, Basel. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Jan 2008 Chris Wallace,Stephen J Newhouse,Peter Braund,Feng Zhang,Martin Tobin,Mario Falchi,Kourosh Ahmadi,Richard J Dobson,Ana Carolina B Marçano,Cother Hajat,Paul Burton,Panagiotis Deloukas,Morris Brown,John M Connell,Anna Dominiczak,G Mark Lathrop,John Webster,Martin Farrall,Tim Spector,Nilesh J Samani,Mark J Caulfield,Patricia B Munroe Many common diseases are accompanied by disturbances in biochemical traits. Identifying the genetic determinants could provide novel insights into disease mechanisms and reveal avenues for developing new therapies. Here, we report a genome-wide association analysis for commonly measured serum and u... ( view more )rine biochemical traits. As part of the WTCCC, 500,000 SNPs genome wide were genotyped in 1955 hypertensive individuals characterized for 25 serum and urine biochemical traits. For each trait, we assessed association with individual SNPs, adjusting for age, sex, and BMI. Lipid measurements were further examined in a meta-analysis of genome-wide data from a type 2 diabetes scan. The most promising associations were examined in two epidemiological cohorts. We discovered association between serum urate and SLC2A9, a glucose transporter (p = 2 x 10(-15)) and confirmed this in two independent cohorts, GRAPHIC study (p = 9 x 10(-15)) and TwinsUK (p = 8 x 10(-19)). The odds ratio for hyperuricaemia (defined as urate >0.4 mMol/l) is 1.89 (95% CI = 1.36-2.61) per copy of common allele. We also replicated many genes previously associated with serum lipids and found previously recognized association between LDL levels and SNPs close to genes encoding PSRC1 and CELSR2 (p = 1 x 10(-7)). The common allele was associated with a 6% increase in nonfasting serum LDL. This region showed increased association in the meta-analysis (p = 4 x 10(-14)). This finding provides a potential biological mechanism for the recent association of this same allele of the same SNP with increased risk of coronary disease. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles European rational approach for the genetics of diabetic complications--EURAGEDIC: patient populations and strategy. Jan 2008 Lise Tarnow,Per-Henrik Groop,Samy Hadjadj,Gbenga Kazeem,Francois Cambien,Michel Marre,Carol Forsblom,Hans-Henrik Parving,David Trégouët,Alexandre Thévard,Martin Farrall,Ivo Gut,Dominique Gauguier,Roger Cox,Fumihiko Matsuda,Mark Lathrop,Nathalie Vionnet,EURAGEDIC Consortium BACKGROUND: Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURA... ( view more )GEDIC study was to address these problems. METHODS: Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n=2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parent-offspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing. RESULTS: In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA(1c), blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA(1c) and smoking as well as pair-wise interactions. CONCLUSIONS: The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in Type 1 diabetic patients. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The C-532T polymorphism of the angiotensinogen gene is associated with pulse pressure: a possible explanation for heterogeneity in genetic association studies of AGT and hypertension. Dec 2007 Michelle Baker,Thahira Rahman,Darroch Hall,Peter J Avery,Bongani M Mayosi,John M C Connell,Martin Farrall,Hugh Watkins,Bernard Keavney BACKGROUND: Many previous studies have investigated whether there is an association between genotypes at the angiotensinogen (AGT) gene and hypertensive status, but few have incorporated quantitative data. Although meta-analyses support a possible effect of AGT variants on blood pressure (BP), subs... ( view more )tantial unexplained between-study heterogeneity has been observed. We hypothesized that a primary effect of AGT variants on arterial stiffness (and thus pulse pressure) might explain such heterogeneity, and tested for such an effect in a family study. METHODS: We studied 1425 individuals from 248 families ascertained through a proband with essential hypertension. BP was measured using 24 h ambulatory monitoring, and polymorphisms of the AGT gene that had been previously associated with hypertension and/or plasma angiotensinogen levels were typed. Pulse pressure was used as a measurement of arterial stiffness. RESULTS: We observed a highly significant association between genotypes at the AGT C-532T polymorphism and pulse pressure (p = 0.00006). Each T allele was associated with a 5% lower pulse pressure (that is, an additive effect). This resulted from opposing genotypic effects to (slightly) lower systolic BP and (slightly) elevate DBP. CONCLUSIONS: These results suggest that genetic variation at the angiotensinogen locus may primarily affect arterial stiffness, and therefore pulse pressure. The heterogeneity between previous genetic studies of AGT and hypertension status could in part be explained by this finding, since case selection criteria based on systolic BP, diastolic BP, or both would result in different levels of selection for the -532T allele. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study. Dec 2007 E M Freel,M Ingram,E C Friel,R Fraser,M Brown,N J Samani,M Caulfield,P Munroe,M Farrall,J Webster,D Clayton,A F Dominiczak,E Davies,J M C Connell BACKGROUND: Aldosterone is an important cardiovascular hormone; 15% of hypertensive subjects have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of the aldosterone synthase gene (CYP11B2) have focused on a single nucleotide polymorphism in the... ( view more ) 5'promoter region (-344 C/T). In normotensive subjects, the T allele associates with raised levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for 11beta-hydroxylase, encoded by the adjacent and homologous gene, CYP11B1. We have speculated that this altered 11beta-hydroxylase efficiency leads to increased ACTH drive to the adrenal gland to maintain cortisol production and reported herein the association between the -344 C/T single nucleotide polymorphism (SNP) and adrenal steroid production in subjects with essential hypertension. METHODS: The CYP11B2-344 C/T polymorphism was genotyped and urinary excretion of adrenal steroid metabolites was measured (by GCMS) in 511 unrelated hypertensives from the Medical Research Council (MRC) British Genetics of Hypertension (BRIGHT) study. RESULTS: Thirty-five per cent of subjects were homozygous for the -344T allele whilst 16% were CC homozygotes. There was no difference in cortisol excretion rate between the two genotype groups but the index of adrenal 11beta-hydroxylation (ratio of tetrahydrodeoxycortisol/total cortisol) was significantly higher in the TT group (P < 0.005) than in the CC group. Excretion rates of the major urinary metabolite of aldosterone (tetrahydroaldosterone) correlated strongly with the ACTH-regulated steroids, cortisol (r = 0.437, P < 0.0001) and total androgen metabolites (r = 0.4, P < 0.0001) in TT but not CC subjects. CONCLUSIONS: Hypertensives homozygous for the -344 T allele of CYP11B2 demonstrate altered 11beta-hydroxylase efficiency (CYP11B1); this is consistent with the hypothesis of a genetically determined increase in adrenal ACTH drive in these subjects. The correlation between excretion of aldosterone and cortisol metabolites and suggests that, in TT subjects, ACTH exerts an important common regulatory influence on adrenal corticosteroid production in subjects with hypertension. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Nov 15, 2007 Stephan Menzel,Jie Jiang,Nicholas Silver,Joy Gallagher,Juliette Cunningham,Gabriela Surdulescu,Mark Lathrop,Martin Farrall,Tim D Spector,Swee Lay Thein Common sequence variants situated between the HBS1L and MYB genes on chromosome 6q23.3 (HMIP) influence the proportion of F cells (erythrocytes that carry measurable amounts of fetal hemoglobin). Since the physiological processes underlying the F-cell variability are thought to be linked to kinetic... ( view more )s of erythrocyte maturation and differentiation, we have investigated the influence of the HMIP locus on other hematologic parameters. Here we show a significant impact of HMIP variability on several types of peripheral blood cells: erythrocyte, platelet, and monocyte counts as well as erythrocyte volume and hemoglobin content in healthy individuals of European ancestry. These results support the notion that changes of F-cell abundance can be an indicator of more general shifts in hematopoietic patterns in humans. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles A genome-wide association study of global gene expression. Oct 2007 Anna L Dixon,Liming Liang,Miriam F Moffatt,Wei Chen,Simon Heath,Kenny C C Wong,Jenny Taylor,Edward Burnett,Ivo Gut,Martin Farrall,G Mark Lathrop,Gonçalo R Abecasis,William O C Cookson We have created a global map of the effects of polymorphism on gene expression in 400 children from families recruited through a proband with asthma. We genotyped 408,273 SNPs and identified expression quantitative trait loci from measurements of 54,675 transcripts representing 20,599 genes in Epst... ( view more )ein-Barr virus-transformed lymphoblastoid cell lines. We found that 15,084 transcripts (28%) representing 6,660 genes had narrow-sense heritabilities (H2) > 0.3. We executed genome-wide association scans for these traits and found peak lod scores between 3.68 and 59.1. The most highly heritable traits were markedly enriched in Gene Ontology descriptors for response to unfolded protein (chaperonins and heat shock proteins), regulation of progression through the cell cycle, RNA processing, DNA repair, immune responses and apoptosis. SNPs that regulate expression of these genes are candidates in the study of degenerative diseases, malignancy, infection and inflammation. We have created a downloadable database to facilitate use of our findings in the mapping of complex disease loci. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Oct 2007 Stephan Menzel,Chad Garner,Ivo Gut,Fumihiko Matsuda,Masao Yamaguchi,Simon Heath,Mario Foglio,Diana Zelenika,Anne Boland,Helen Rooks,Steve Best,Tim D Spector,Martin Farrall,Mark Lathrop,Swee Lay Thein F cells measure the presence of fetal hemoglobin, a heritable quantitative trait in adults that accounts for substantial phenotypic diversity of sickle cell disease and beta thalassemia. We applied a genome-wide association mapping strategy to individuals with contrasting extreme trait values and m... ( view more )apped a new F cell quantitative trait locus to BCL11A, which encodes a zinc-finger protein, on chromosome 2p15. The 2p15 BCL11A quantitative trait locus accounts for 15.1% of the trait variance. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Sep 4, 2007 Peng Y Woon,Pamela J Kaisaki,José Bragança,Marie-Thérèse Bihoreau,Jonathan C Levy,Martin Farrall,Dominique Gauguier Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encoding Bmal1 is located within hypertension susceptibility loci. We anal... ( view more )yzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show that Bmal1 maps close to a region genetically divergent between SHR and its normotensive (Wistar-Kyoto) counterpart. Bmal1 sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome. ( view less ) View Full Abstract View Article Details   Related Articles Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension. Sep 2007 Ana Carolina Braga Marçano,Beverley Burke,Johannie Gungadoo,Chris Wallace,Pamela J Kaisaki,Peng Y Woon,Martin Farrall,David Clayton,Morris Brown,Anna Dominiczak,John M Connell,John Webster,Mark Lathrop,Mark Caulfield,Nilesh Samani,Dominique Gauguier,Patricia B Munroe BACKGROUND: Inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of metabolic syndrome... ( view more ). In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension. OBJECTIVE AND METHODS: To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort. RESULTS: We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p>0.1). CONCLUSION: These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension in metabolic syndrome patients specifically. ( view less ) View Full Abstract View Article Details   Related Articles Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Jul 26, 2007 Miriam F Moffatt,Michael Kabesch,Liming Liang,Anna L Dixon,David Strachan,Simon Heath,Martin Depner,Andrea von Berg,Albrecht Bufe,Ernst Rietschel,Andrea Heinzmann,Burkard Simma,Thomas Frischer,Saffron A G Willis-Owen,Kenny C C Wong,Thomas Illig,Christian Vogelberg,Stephan K Weiland,Erika von Mutius,Gonçalo R Abecasis,Martin Farrall,Ivo G Gut,G Mark Lathrop,William O C Cookson Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994... ( view more ) patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10(-12). In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10(-22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. ( view less ) View Full Abstract View Article Details   Related Articles Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Jul 3, 2007 Swee Lay Thein,Stephan Menzel,Xu Peng,Steve Best,Jie Jiang,James Close,Nicholas Silver,Ageliki Gerovasilli,Chen Ping,Masao Yamaguchi,Karin Wahlberg,Pinar Ulug,Tim D Spector,Chad Garner,Fumihiko Matsuda,Martin Farrall,Mark Lathrop Individual variation in fetal hemoglobin (HbF, alpha(2)gamma(2)) response underlies the remarkable diversity in phenotypic severity of sickle cell disease and beta thalassemia. HbF levels and HbF-associated quantitative traits (e.g., F cell levels) are highly heritable. We have previously mapped a ... ( view more )major quantitative trait locus (QTL) controlling F cell levels in an extended Asian-Indian kindred with beta thalassemia to a 1.5-Mb interval on chromosome 6q23, but the causative gene(s) are not known. The QTL encompasses several genes including HBS1L, a member of the GTP-binding protein family that is expressed in erythroid progenitor cells. In this high-resolution association study, we have identified multiple genetic variants within and 5' to HBS1L at 6q23 that are strongly associated with F cell levels in families of Northern European ancestry (P = 10(-75)). The region accounts for 17.6% of the F cell variance in northern Europeans. Although mRNA levels of HBS1L and MYB in erythroid precursors grown in vitro are positively correlated, only HBS1L expression correlates with high F cell alleles. The results support a key role for the HBS1L-related genetic variants in HbF control and illustrate the biological complexity of the mechanism of 6q QTL as a modifier of fetal hemoglobin levels in the beta hemoglobinopathies. ( view less ) View Full Abstract View Article Details   Related Articles A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly. Jun 2007 Moises Mercado,Fatima Borges,Hakim Bouterfa,Tien-Chun Chang,Alberto Chervin,Andrew J Farrall,Attila Patocs,Stephan Petersenn,Jan Podoba,Mitra Safari,Joanna Wardlaw,SMS995B2401 Study Group OBJECTIVE: To evaluate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of acromegaly. DESIGN AND PATIENTS: Ninety-eight previously untreated acromegalics were recruited into this prospective multicentre study. A total of 68 patients... ( view more ) successfully completed 48 weeks of the study period, received 12 doses of octreotide LAR 10-30 mg every 4 weeks, and constituted the population used for this analysis. MEASUREMENTS AND RESULTS: A clinically relevant reduction (i.e. to < or = 5 microg/l) in mean GH (mGH) was recorded in 72% of patients after 24 weeks of treatment, and 42% reached a 'safe' GH value (< or = 2.5 microg/l). At week 48, 16 more patients were considered partial GH responders (GH > 2.5 microg/l and < or = 5 microg/l) and 44% had reached a GH level < or = 2.5 microg/l. IGF-1 levels normalized in 38% and 34% of patients after 24 and 48 weeks of treatment, respectively. At study completion, 10 patients (14.7%) who had not normalized their IGF-1 levels had achieved at least a 50% decrement in this marker. In eight microadenoma patients, tumour volume decreased from a mean baseline level of 298 +/- 145 mm3 to 139 +/- 94 mm3 after 24 weeks and to 99 +/- 70 mm3 after 48 weeks of therapy. In 60 patients with macroadenoma, the corresponding values were 3885 +/- 5077 mm3 at baseline and 2723 +/- 3435 and 2406 +/- 3207 mm3 after 24 and 48 weeks, respectively. At weeks 24 and 48, a significant (> 20%) tumour volume reduction was reported in 63% and 75% of patients, respectively. A reduction in the severity of symptoms of acromegaly was observed early in treatment and was maintained throughout the study period. CONCLUSION: Octreotide LAR represents a viable alternative to surgery for primary treatment of acromegaly leading to a progressive regression of tumour volume, a sustained control of biochemical abnormalities and an adequate relief of symptoms of the disease. ( view less ) View Full Abstract View Article Details View Coded Data Related Articles Association between angiotensin-converting enzyme gene polymorphisms and diabetic nephropathy: case-control, haplotype, and family-based study in three European populations. Apr 2007 Samy Hadjadj,Lise Tarnow,Carol Forsblom,Gbenga Kazeem,Michel Marre,Per-Henrik Groop,Hans-Henrik Parving,François Cambien,David A Tregouet,Ivo G Gut,Alexandre Théva,Dominique Gauguier,Martin Farrall,Roger Cox,Fumihiko Matsuda,Mark Lathrop,Nathalie Hager-Vionnet,EURAGEDIC (European Rational Approach for Genetics of Diabetic Complications) Study Group Angiotensin 1-converting enzyme gene (ACE) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients ... ( view more )(with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [> or =15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed of 244 trios with DN probands and 288 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C, rs4311-T, Insertion/deletion (I/D or rs1799752)-D, rs4366-G, and rs12449782-G alleles were associated with an increased risk for DN, homogeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366_G and rs12449782_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmission to DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN; these findings were not confirmed in a family-based association study. This study population is suitable to search for additional candidate genes for DN. ( view less ) View Full Abstract View Article Details   Related Articles Factors influencing the detection of early CT signs of cerebral ischemia: an internet-based, international multiobserver study. Apr 2007 Joanna M Wardlaw,Andrew J Farrall,David Perry,Rudiger von Kummer,Orell Mielke,Thierry Moulin,Alfonso Ciccone,Michael Hill,Acute Cerebral CT Evaluation of Stroke Study (ACCESS) Study Group BACKGROUND AND PURPOSE: Early CT signs of cerebral ischemia are subtle. Little is known of which factors influence the detection of infarct signs. We compared neuroradiologists' scan readings with those of other specialists involved in the care of stroke patients. METHODS: We used the Internet to s... ( view more )how 63 CT scans, all acquired <6 hours after stroke and representing different patient ages, times to scanning, stroke severity, and early CT signs of ischemia to physicians involved in stroke care. They completed a structured scan interpretation proforma over the Internet. We compared the detection of early ischemic signs stratified by severity and the effect of prior stroke between different specialties. RESULTS: Among 207 observers, neuroradiologists saw significantly more of "any early ischemic changes" than did stroke physicians, general radiologists, geriatricians, or neurologists (all P<0.0001), predominantly due to neuroradiologists' greater detection of "mild" hypoattenuation or swelling. Detection of "severe" hypoattenuation or swelling, and hyperattenuated arteries did not differ between specialties. Old infarcts impaired recognition of early ischemic signs. Non-neuroradiologists did not "over-call" signs. Years of scan-reading experience did not account for these differences, but neuroradiologists took, on average, 30 seconds longer to read each scan than did most other specialists (P<0.0001). CONCLUSIONS: Non-neuroradiologists should realize that they are unlikely to over-call signs, that old infarcts may distract them from seeing early ischemic signs, and read stroke CT scans more slowly, as these factors may help them perform more like neuroradiologists. ( view less ) View Full Abstract View Article Details   Related Articles Multiple QTL influence the serum Lp(a) concentration: a genome-wide linkage screen in the PROCARDIS study. Feb 2007 Simona Barlera,Claudia Specchia,Martin Farrall,Benedetta D Chiodini,Maria Grazia Franzosi,Stephan Rust,Fiona Green,Enrico B Nicolis,John Peden,Gerd Assmann,Rory Collins,Anders Hamsten,Gianni Tognoni,Hugh Watkins,PROCARDIS Consortium The serum concentration of lipoprotein Lp (a) is known to be highly heritable and associated with cardiovascular risk. A genome-wide variance component linkage analysis was performed to localise quantitative trait loci (QTLs) influencing Lp(a) levels in a large cohort collected in the PROCARDIS cor... ( view more )onary heart disease study. Highly significant linkage was detected at the previously described LP(a) locus on chromosome 6q27 (LOD 108). Taking into account the effect of the locus detected on chromosome 6, a highly significant LOD score was detected on chromosome 13q22-31 (LOD 7.0). Another significant region of linkage was observed on chromosomes 11p14-15 (LOD 3.5).The significant peak at 13q22-31 shows an essential overlap with a locus modulating cholesterol in familial hypercholesterolemia. If the gene underlying these loci is the same, it will be a promising candidate target for manipulating LDL-cholesterol and Lp(a). We also detected linkage at a previously identified locus influencing Lp(a) on chromosome 1q23 (LOD 1.5). Our findings provide new and confirmatory information about genomic regions involved in the quantitative variation of Lp(a) and serve as a basis for further studies of candidate genes in these regions. ( view less ) View Full Abstract View Article Details   Related Articles Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency. Jan 2007 Marianne Barr,Scott M MacKenzie,Elaine C Friel,Christine D Holloway,Donna M Wilkinson,Nick J R Brain,Mary C Ingram,Robert Fraser,Morris Brown,Nilesh J Samani,Mark Caulfield,Patricia B Munroe,Martin Farrall,John Webster,David Clayton,Anna F Dominiczak,John M C Connell,Eleanor Davies The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11beta-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11beta-hydroxylase gene (CYP11B1) and arises thr... ( view more )ough linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the -344 and intron conversion variants. Eighty-three variants associated with -344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (-1889 G/T and -1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the -1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11beta-hydroxylase efficiency. A similar pattern was observed for the -1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11beta-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1. ( view less ) View Full Abstract View Article Details   Related Articles Page 1 of 7 1 2 3 4 > Last >> (161 articles found)

      
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