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A Deletion at ADAMTS9-MAGI1 Locus Is Associated with Psoriatic Arthritis

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A Deletion at ADAMTS9-MAGI1 Locus Is Associated with Psoriatic Arthritis View metadata, citation and similar Downloadedpapers at core.ac.uk from http://ard.bmj.com/ on November 29, 2016 - Published by group.bmj.com brought to you by CORE provided by Diposit Digital de la Universitat de Barcelona Clinical and epidemiological research EXTENDED REPORT A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk Antonio Julià,1 José Antonio Pinto,2 Jordi Gratacós,3 Rubén Queiró,4 Carlos Ferrándiz,5 Eduardo Fonseca,6 Carlos Montilla,7 Juan Carlos Torre-Alonso,8 Lluís Puig,9 José Javier Pérez Venegas,10 Antonio Fernández Nebro,11 Emilia Fernández,12 Santiago Muñoz-Fernández,13 Esteban Daudén,14 Carlos González,15 Daniel Roig,16 José Luís Sánchez Carazo,17 Pedro Zarco,18 Alba Erra,19 José Luís López Estebaranz,20 Jesús Rodríguez,21 DavidMorenoRamírez,22 Pablo de la Cueva,23 Francisco Vanaclocha,24 Enrique Herrera,25 Santos Castañeda,26 Esteban Rubio,27 Georgina Salvador,28 César Díaz-Torné,29 Ricardo Blanco,30 Alfredo Willisch Domínguez,31 José Antonio Mosquera,32 Paloma Vela,33 Jesús Tornero,34 Simón Sánchez-Fernández,35 Héctor Corominas,16 Julio Ramírez,36 María López-Lasanta,1 Raül Tortosa,1 Nuria Palau,1 Arnald Alonso,1 Andrés C García-Montero,37 Josep Lluís Gelpí,38 Laia Codó,39 Kenneth Day,39 Devin Absher,39 Richard M Myers,39 Juan D Cañete,36 Sara Marsal1 Handling editor Tore K Kvien 12 ▸ Additional material is ABSTRACT psoriasis. To date, genome-wide association published online only. To view Objective Copy number variants (CNVs) have been studies (GWAS) as well as candidate gene studies please visit the journal online associated with the risk to develop multiple autoimmune have shown that both diseases share a substantial (http://dx.doi.org/10.1136/ annrheumdis-2014-207190). diseases. Our objective was to identify CNVs associated genetic component. However, sibling recurrence with the risk to develop psoriatic arthritis (PsA) using a rates (λs) are much higher for PsA than psoriasis For numbered affiliations see 3–5 genome-wide analysis approach. (PsA λs∼37 vs psoriasis λs∼7), indicating that end of article. Methods A total of 835 patients with PsA and 1498 additional, perhaps disease-specific, risk factors fi Correspondence to healthy controls were genotyped for CNVs using the need to be identi ed. Professor Sara Marsal, Illumina HumanHap610 BeadChip genotyping platform. GWAS based on single-nucleotide polymorph- Rheumatology Research Group, Genomic CNVs were characterised using CNstream isms (SNPs) have been highly successful in identify- ’ Vall d Hebron University analysis software and analysed for association using the ing >30 loci associated with psoriasis and PsA Hospital, Pg Vall d’Hebron, – χ2 test. The most significant genomic CNV associations susceptibility.6 8 The cumulative risk exerted by 119-129, Barcelona 08035, 9 Spain; [email protected] with PsA risk were independently tested in a validation these loci, however, is <50%, and additional and Dr Juan D Cañete, sample of 1133 patients with PsA and 1831 healthy genetic factors still need to be identified in order to Rheumatology Department, controls. In order to test for the specificity of the variants explain the missing heritability. Strategies to com- Hospital Clínic i Provincial and with PsA aetiology, we also analysed the association to plete the characterisation of the genetic architecture IDIBAPS, c/Villarroel 170, 08036, Barcelona, Spain; a cohort of 822 patients with purely cutaneous psoriasis of psoriasis and PsA include the use of large sample [email protected] (PsC). sizes or the combination of different studies Results A total of 165 common CNVs were identified through metaanalysis,10 the deep sequence charac- SM and JDC are co- in the genome-wide analysis. We found a highly terisation to identify rare variants with large effect corresponding authors. significant association of an intergenic deletion between sizes11 and, also, the analysis of other types of Received 19 December 2014 ADAMTS9 and MAGI1 genes on chromosome 3p14.1 genetic variation that cannot be completely cap- Revised 23 April 2015 (p=0.00014). Using the independent patient and control tured by SNP-based genotyping platforms such as Accepted 23 April 2015 cohort, we validated the association between ADAMTS9- copy number variants (CNVs). Published Online First MAGI1 deletion and PsA risk (p=0.032). Using next- CNVs are fragments of DNA with sizes that range 19 May 2015 generation sequencing, we characterised the 26 kb from hundreds of bases to several megabases, and associated deletion. Finally, analysing the PsC cohort we that can either be absent (ie, deletions), repeated a found a lower frequency of the deletion compared with certain number of times (ie, amplifications) or even the PsA cohort (p=0.0088) and a similar frequency to rearranged.12 Psoriasis was one of the first chronic that of healthy controls (p>0.3). inflammatory diseases where CNVs were found to Conclusions The present genome-wide scan for CNVs be associated with the disease risk. The amplifica- associated with PsA risk has identified a new deletion tions of the β-defensin genes on 8p23.1 region13 associated with disease risk and which is also differential and the deletion affecting LCE3B and LCE3C 14 ▸ http://dx.doi.org/10.1136/ from PsC risk. genes have been clearly associated with psoriasis annrheumdis-2014-207187 aetiology. The association of these CNVs with PsA 215 To cite: Julià A, Pinto JA, aetiology, however, is still not clear, suggesting Gratacós J, et al. Ann INTRODUCTION that they could participate in the chronic inflamma- Rheum Dis 2015;74: Psoriatic arthritis (PsA) is a chronic inflammatory tory processes in the skin rather than in the patho- – 1875 1881. arthritis that affects 10–30% of patients with logical process occurring in the joint. Julià A, et al. Ann Rheum Dis 2015;74:1875–1881. doi:10.1136/annrheumdis-2014-207190 1875 Downloaded from http://ard.bmj.com/ on November 29, 2016 - Published by group.bmj.com Clinical and epidemiological research In the present study, we have performed the first genome- patients with plaque psoriasis affecting torso and/or extremities wide analysis of CNVs in PsA. We have first analysed a discovery and with at least one year of duration were included. Patients panel of 835 patients with PsA and 1498 healthy controls from with a single clinical localisation of plaque psoriasis (ie, scalp, the Spanish population using a microarray platform. The CNVs face, palmoplantar), with exclusively inverse plaque psoriasis or showing a more significant association to PsA risk were subse- with an inflammatory bowel disease, were excluded from the quently selected and validated in an independent cohort of study. Finally, psoriasis patients diagnosed with PsA by a 1133 patients with PsA and 1831 healthy controls. In order to rheumatologist were excluded from this group. test for the specificity of the CNV association with PsA aeti- ology, we have also analysed a set of 822 psoriasis patients Genome-wide CNV analysis without arthritis. Using this approach, we have identified a new We performed a CNV genome-wide scan by using Illumina deletion associated with PsA risk that is not associated with 610Quad Beadchips (Illumina, San Diego, California, USA), purely cutaneous psoriasis (PsC). which contains a total of 620 901 probes. Sample genotyping was performed at the HudsonAlpha Institute for Biotechnology PATIENTS AND METHODS (Alabama, USA). After excluding mitochondrial as well as X and Study subjects Y chromosome SNPs, a total of 600 470 probes were considered To identify new loci associated with psoriasis risk using the for GWAS CNV analysis. GWAS approach, we recruited 835 patients with PsA and 1498 Before proceeding to perform PsA risk analysis, we performed healthy controls from the Spanish population. Patient and several quality control analysis steps. First, only those samples control individuals were obtained by the Immune-Mediated that had a >95% genotype completion rate were considered for Inflammatory Disease Consortium (IMIDC).16 The IMIDC is a analysis (99% of samples). Second, we used the SNPs genotype Spanish biomedical research collaboration project that includes information to estimate the main axes of variation using the biomedical and clinical researchers on rheumatology, dermatol- principal component analysis implemented in the Eigenstrat ogy and gastroenterology, and that is devoted to the study of software.19 With this approach, individuals showing a high devi- prevalent autoimmune diseases. In the present study, a total of ation in any of the 10 top principal axes of variation were con- 26 rheumatology departments—15 in the GWAS stage and 11 sidered outliers and were consequently removed (>6 SDs from additional in the replication stage—and 11 dermatology depart- the centre of each component, n=42 outliers). Online supple- ments from different university hospitals in Spain participated mentary figure S1 shows the patient with PsA and control distri- in the patient recruitment and clinical data collection. All butions according to the first and second principal components patients with PsA included in this study had a clinical diagnosis after excluding the outliers. made by a consultant rheumatologist. All patients with PsA were Since CNV genotyping is subject to more technical biases diagnosed according to the Classification Criteria for Psoriatic than SNP genotyping, several additional quality control filters Arthritis criteria,17 were >18 years old—although the disease must be applied to the GWAS data. Following previous GWAS could have started earlier in life—and had at least 1 year of evo- CNV studies,20 samples with a substantial deviation from the lution of the disease. Exclusion criteria for the present study mean log Ratio (|m log R ratio| > 0.1) or with an excessive were (i) presence of any other inflammatory joint disease, (ii) variability (σ log R ratio > 0.2), were excluded (n=556 indivi- presence of any inflammatory bowel disease and (iii) positivity duals, 23.8%).
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