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Michaela Fakiola,
Amy Strange,
Heather J Cordell,
E Nancy Miller,
Matti Pirinen,
Zhan Su,
Anshuman Mishra,
Sanjana Mehrotra,
Gloria R Monteiro,
Gavin Band, [......],
Mary E Wilson,
Panos Deloukas,
Leena Peltonen,
Frank Christiansen,
Campbell Witt,
Selma M B Jeronimo,
Shyam Sundar,
Chris C A Spencer,
Jenefer M Blackwell,
Peter Donnelly
[show abstract]
[hide abstract]
ABSTRACT: To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P(combined) = 2.76 × 10(-17) and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.
Nature Genetics 01/2013; · 35.53 Impact Factor
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Steve Eyre,
John Bowes,
Dorothée Diogo,
Annette Lee,
Anne Barton,
Paul Martin,
Alexandra Zhernakova,
Eli Stahl,
Sebastien Viatte,
Kate McAllister, [......],
Miguel A Gonzalez-Gay,
Luis Rodriguez-Rodriguez,
Lisbeth Arlsetig,
Javier Martin,
Solbritt Rantapää-Dahlqvist,
Robert M Plenge,
Soumya Raychaudhuri,
Lars Klareskog,
Peter K Gregersen,
Jane Worthington
[show abstract]
[hide abstract]
ABSTRACT: Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
Nature Genetics 11/2012; · 35.53 Impact Factor
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Lam C Tsoi,
Sarah L Spain,
Jo Knight,
Eva Ellinghaus,
Philip E Stuart,
Francesca Capon,
Jun Ding,
Yanming Li,
Trilokraj Tejasvi,
Johann E Gudjonsson, [......],
Matthew Waller,
Paul Weston,
Sara Widaa,
Pamela Whittaker,
Rajan P Nair,
Andre Franke,
Jonathan N W N Barker,
Goncalo R Abecasis,
James T Elder,
Richard C Trembath
[show abstract]
[hide abstract]
ABSTRACT: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
Nature Genetics 11/2012; · 35.53 Impact Factor
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Zhan Su,
Laura J Gay,
Amy Strange,
Claire Palles,
Gavin Band,
David C Whiteman,
Francesco Lescai, Cordelia Langford,
Manoj Nanji,
Sarah Edkins, [......],
Paul Moayyedi,
John de Caestecker,
Hugh Barr,
Elia Stupka,
Thomas L Vaughan,
Leena Peltonen,
Chris C A Spencer,
Ian Tomlinson,
Peter Donnelly,
Janusz A Z Jankowski
[show abstract]
[hide abstract]
ABSTRACT: Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
Nature Genetics 09/2012; 44(10):1131-1136. · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.
Nature Genetics 03/2012; 44(5):502-10. · 35.53 Impact Factor
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Céline Bellenguez,
Steve Bevan,
Andreas Gschwendtner,
Chris C A Spencer,
Annette I Burgess,
Matti Pirinen,
Caroline A Jackson,
Matthew Traylor,
Amy Strange,
Zhan Su, [......],
Agnieszka Slowik,
Matthew Walters,
Jonathan Rosand,
Pankaj Sharma,
Martin Farrall,
Cathie L M Sudlow,
Peter M Rothwell,
Martin Dichgans,
Peter Donnelly,
Hugh S Markus
[show abstract]
[hide abstract]
ABSTRACT: Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
Nature Genetics 01/2012; 44(3):328-33. · 35.53 Impact Factor
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Gosia Trynka,
Karen A Hunt,
Nicholas A Bockett,
Jihane Romanos,
Vanisha Mistry,
Agata Szperl,
Sjoerd F Bakker,
Maria Teresa Bardella,
Leena Bhaw-Rosun,
Gemma Castillejo, [......],
Bozena Cukrowska,
Elena Urcelay,
Jose Ramon Bilbao,
M Luisa Mearin,
Donatella Barisani,
Jeffrey C Barrett,
Vincent Plagnol,
Panos Deloukas,
Cisca Wijmenga,
David A van Heel
[show abstract]
[hide abstract]
ABSTRACT: Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.
Nature Genetics 11/2011; 43(12):1193-201. · 35.53 Impact Factor
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Stephen Sawcer,
Garrett Hellenthal,
Matti Pirinen,
Chris C A Spencer,
Nikolaos A Patsopoulos,
Loukas Moutsianas,
Alexander Dilthey,
Zhan Su,
Colin Freeman,
Sarah E Hunt, [......],
Jan Hillert,
Adrian J Ivinson,
Philip L De Jager,
Leena Peltonen,
Graeme J Stewart,
David A Hafler,
Stephen L Hauser,
Gil McVean,
Peter Donnelly,
Alastair Compston
[show abstract]
[hide abstract]
ABSTRACT: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Nature 08/2011; 476(7359):214-9. · 36.28 Impact Factor
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The Australo-Anglo-American Spondyloarthritis Consortium (TASC,
the Wellcome Trust Case Control Consortium,
David M Evans,
Chris C A Spencer,
Jennifer J Pointon,
Zhan Su,
David Harvey,
Grazyna Kochan,
Udo Oppermann,
Alexander Dilthey, [......],
Matthew Waller,
Paul Weston,
Pamela Whittaker,
Sara Widaa,
Nicholas W Wood,
Gilean McVean,
John D Reveille,
B Paul Wordsworth,
Matthew A Brown,
Peter Donnelly
Nature Genetics 07/2011; 43(8):761-767. · 35.53 Impact Factor
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Kaixin Zhou,
Celine Bellenguez,
Chris C A Spencer,
Amanda J Bennett,
Ruth L Coleman,
Roger Tavendale,
Simon A Hawley,
Louise A Donnelly,
Chris Schofield,
Christopher J Groves, [......],
Helen Colhoun,
Andrew D Morris,
Calum Sutherland,
D Grahame Hardie,
Leena Peltonen,
Mark I McCarthy,
Rury R Holman,
Colin N A Palmer,
Peter Donnelly,
Ewan R Pearson
[show abstract]
[hide abstract]
ABSTRACT: Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.
Nature Genetics 02/2011; 43(2):117-20. · 35.53 Impact Factor
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Chris C A Spencer,
Vincent Plagnol,
Amy Strange,
Michelle Gardner,
Coro Paisan-Ruiz,
Gavin Band,
Roger A Barker,
Celine Bellenguez,
Kailash Bhatia,
Hannah Blackburn, [......],
Simon Potter,
Anna Rautanen,
Stephen J Sawcer,
Zhan Su,
Richard C Trembath,
Ananth C Viswanathan,
Nigel W Williams,
Huw R Morris,
Peter Donnelly,
Nicholas W Wood
[show abstract]
[hide abstract]
ABSTRACT: We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10(-4)). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10(-10)) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.
Human Molecular Genetics 01/2011; 20(2):345-53. · 7.64 Impact Factor
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David M Evans,
Chris C A Spencer,
Jennifer J Pointon,
Zhan Su,
David Harvey,
Grazyna Kochan,
Udo Oppermann,
Udo Opperman,
Alexander Dilthey,
Matti Pirinen, [......],
Matthew Waller,
Paul Weston,
Pamela Whittaker,
Sara Widaa,
Nicholas W Wood,
Gilean McVean,
John D Reveille,
B Paul Wordsworth,
Matthew A Brown,
Peter Donnelly
[show abstract]
[hide abstract]
ABSTRACT: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
Nature Genetics 01/2011; 43(8):761-7. · 35.53 Impact Factor
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Karen A Hunt,
Deborah J Smyth,
Tobias Balschun,
Maria Ban,
Vanisha Mistry,
Tariq Ahmad,
Vidya Anand,
Jeffrey C Barrett,
Leena Bhaw-Rosun,
Nicholas A Bockett, [......],
Stephen C L Gough,
Stephen Sawcer,
Cisca Wijmenga,
Miles Parkes,
Francesco Cucca,
Andre Franke,
Panos Deloukas,
Stephen S Rich,
John A Todd,
David A van Heel
Nature Genetics 01/2011; 44(1):3-5. · 35.53 Impact Factor
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Alison H Goodall,
Philippa Burns,
Isabelle Salles,
Iain C Macaulay,
Chris I Jones,
Diego Ardissino,
Bernard de Bono,
Sarah L Bray,
Hans Deckmyn,
Frank Dudbridge, [......],
Marie N O'Connor,
Catherine M Rice,
Derek Stemple,
Jonathan Stephens,
Mieke D Trip,
Jaap-Jan Zwaginga,
Nilesh J Samani,
Nicholas A Watkins,
Patricia B Maguire,
Willem H Ouwehand
[show abstract]
[hide abstract]
ABSTRACT: Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.
Blood 11/2010; 116(22):4646-56. · 9.90 Impact Factor
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Amy Strange,
Francesca Capon,
Chris C A Spencer,
Jo Knight,
Michael E Weale,
Michael H Allen,
Anne Barton,
Gavin Band,
Céline Bellenguez,
Judith G M Bergboer, [......],
Christopher E M Griffiths,
Juha Kere,
André Reis,
Gilean McVean,
David M Evans,
Matthew A Brown,
Jonathan N Barker,
Leena Peltonen,
Peter Donnelly,
Richard C Trembath
[show abstract]
[hide abstract]
ABSTRACT: To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
Nature Genetics 11/2010; 42(11):985-90. · 35.53 Impact Factor
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Clare Turnbull,
Shahana Ahmed,
Jonathan Morrison,
David Pernet,
Anthony Renwick,
Mel Maranian,
Sheila Seal,
Maya Ghoussaini,
Sarah Hines,
Catherine S Healey, [......],
Mieke Schutte,
Ans van den Ouweland,
Richard Houlston,
Gillian Ross, Cordelia Langford,
Paul D P Pharoah,
Michael R Stratton,
Alison M Dunning,
Nazneen Rahman,
Douglas F Easton
[show abstract]
[hide abstract]
ABSTRACT: Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
Nature Genetics 06/2010; 42(6):504-7. · 35.53 Impact Factor
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Pawandeep Dhami,
Alexander W Bruce,
Johanna H Jim,
Shane C Dillon,
Amanda Hall,
Jonathan L Cooper,
Nicolas Bonhoure,
Kelly Chiang,
Peter D Ellis, Cordelia Langford,
Robert M Andrews,
David Vetrie
[show abstract]
[hide abstract]
ABSTRACT: The SCL (TAL1) transcription factor is a critical regulator of haematopoiesis and its expression is tightly controlled by multiple cis-acting regulatory elements. To elaborate further the DNA elements which control its regulation, we used genomic tiling microarrays covering 256 kb of the human SCL locus to perform a concerted analysis of chromatin structure and binding of regulatory proteins in human haematopoietic cell lines. This approach allowed us to characterise further or redefine known human SCL regulatory elements and led to the identification of six novel elements with putative regulatory function both up and downstream of the SCL gene. They bind a number of haematopoietic transcription factors (GATA1, E2A LMO2, SCL, LDB1), CTCF or components of the transcriptional machinery and are associated with relevant histone modifications, accessible chromatin and low nucleosomal density. Functional characterisation shows that these novel elements are able to enhance or repress SCL promoter activity, have endogenous promoter function or enhancer-blocking insulator function. Our analysis opens up several areas for further investigation and adds new layers of complexity to our understanding of the regulation of SCL expression.
PLoS ONE 01/2010; 5(2):e9059. · 4.09 Impact Factor
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Pawandeep Dhami,
Peter Saffrey,
Alexander W Bruce,
Shane C Dillon,
Kelly Chiang,
Nicolas Bonhoure,
Christoph M Koch,
Jackie Bye,
Keith James,
Nicola S Foad,
Peter Ellis,
Nicholas A Watkins,
Willem H Ouwehand, Cordelia Langford,
Robert M Andrews,
Ian Dunham,
David Vetrie
[show abstract]
[hide abstract]
ABSTRACT: It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons ("exon-intron marking"), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing.
PLoS ONE 01/2010; 5(8):e12339. · 4.09 Impact Factor
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Jeffrey C Barrett,
James C Lee,
Charles W Lees,
Natalie J Prescott,
Carl A Anderson,
Anne Phillips,
Emma Wesley,
Kirstie Parnell,
Hu Zhang,
Hazel Drummond, [......],
Paul Weston,
Sara Widaa,
Pamela Whittaker,
Antony P Attwood,
Jonathan Stephens,
Jennifer Sambrook,
Willem H Ouwehand,
Wendy L McArdle,
Susan M Ring,
David P Strachan
[show abstract]
[hide abstract]
ABSTRACT: Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.
Nature Genetics 11/2009; 41(12):1330-4. · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Acknowledgement of the breadth of T-cell pleiotropy has provoked increasing interest in the degree to which functional responsiveness is elicited by environmental cues versus differentiation. This is particularly relevant for young animals requiring rapid responses to acute environmental exposure. In young mice, gammadelta T cells are disproportionately important for immuno-protection. To examine the situation in humans, we compared populations and clones of T cells from term and preterm babies, and adults. By comparison with alphabeta T cells, neonate-derived gammadelta cells show stronger, pleiotropic functional responsiveness, and lack signatory deficits in IFN-gamma production. Emphasising the acquisition of functional competence in utero, IFN-gamma was produced by gammadelta cells sampled from premature births, and, although one month's post-partum environmental exposure invariably increased their TNF-alpha production, it had no consistent effect on IFN-gamma or IL-2. In sum, gammadelta cells seem well positioned at birth to contribute to immuno-protection and immuno-regulation, possibly compensating for selective immaturity in the alphabeta compartment. With regard to the susceptibilities of preterm babies to viral infection, gammadelta cells from preterm neonates were commonly impaired in Toll-like receptor-3 and -7 expression and compared with cells from term babies failed to optimise cytokine production in response to coincident TCR and TLR agonists.
European Journal of Immunology 07/2009; 39(7):1794-806. · 5.10 Impact Factor
