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Nature medicine 01/2012; 18(1):48-53. · 27.14 Impact Factor
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George Kollias,
Piyi Papadaki,
Florence Apparailly,
Margriet J Vervoordeldonk,
Rikard Holmdahl,
Vera Baumans,
Christian Desaintes,
James Di Santo,
Jörg Distler,
Paul Garside, [......],
Lars Klareskog,
Iain McInnes,
Ioannis Ragoussis,
Georg Schett,
Bert 't Hart,
Paul P Tak, Rene Toes,
Wim van den Berg,
Wolfgang Wurst,
Steffen Gay
[show abstract]
[hide abstract]
ABSTRACT: The development of novel treatments for rheumatoid arthritis (RA) requires the interplay between clinical observations and studies in animal models. Given the complex molecular pathogenesis and highly heterogeneous clinical picture of RA, there is an urgent need to dissect its multifactorial nature and to propose new strategies for preventive, early and curative treatments. Research on animal models has generated new knowledge on RA pathophysiology and aetiology and has provided highly successful paradigms for innovative drug development. Recent focus has shifted towards the discovery of novel biomarkers, with emphasis on presymptomatic and emerging stages of human RA, and towards addressing the pathophysiological mechanisms and subsequent efficacy of interventions that underlie different disease variants. Shifts in the current paradigms underlying RA pathogenesis have also led to increased demand for new (including humanised) animal models. There is therefore an urgent need to integrate the knowledge on human and animal models with the ultimate goal of creating a comprehensive 'pathogenesis map' that will guide alignment of existing and new animal models to the subset of disease they mimic. This requires full and standardised characterisation of all models at the genotypic, phenotypic and biomarker level, exploiting recent technological developments in 'omics' profiling and computational biology as well as state of the art bioimaging. Efficient integration and dissemination of information and resources as well as outreach to the public will be necessary to manage the plethora of data accumulated and to increase community awareness and support for innovative animal model research in rheumatology.
Annals of the rheumatic diseases 05/2011; 70(8):1357-62. · 8.11 Impact Factor
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Alexandra Zhernakova,
Eli A Stahl,
Gosia Trynka,
Soumya Raychaudhuri,
Eleanora A Festen,
Lude Franke,
Harm-Jan Westra,
Rudolf S N Fehrmann,
Fina A S Kurreeman,
Brian Thomson, [......],
Piet L C M van Riel,
Yonghong Li,
Paul I W de Bakker,
Peter K Gregersen,
Jane Worthington,
Katherine A Siminovitch,
Lars Klareskog,
Tom W J Huizinga,
Cisca Wijmenga,
Robert M Plenge
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ABSTRACT: Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) = 1.2 × 10(-12)), rs864537 near CD247 (P(combined) = 2.2 × 10(-11)), rs2298428 near UBE2L3 (P(combined) = 2.5 × 10(-10)), and rs11203203 near UBASH3A (P(combined) = 1.1 × 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
PLoS Genetics 02/2011; 7(2):e1002004. · 8.69 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
