Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study

Introduction Behcet's disease is a chronic systemic inflammatory disease that remains incompletely understood. Herein, we perform the first genome-wide association study in Behcet's disease

PTPN22 gene polymorphism in Takayasu's arteritis

Objective. Takayasu's arteritis (TA) is a chronic, rare granulomatous panarteritis of unknown aetiology involving mainly the aorta and its major branches. In this study, genetic susceptibility to TA has been investigated by screening the functional single nucleotide polymorphism (SNP) of PTPN22 gene encoding the lymphoid-specific protein tyrosine phosphatase. Methods. Totally, 181 patients with TA and 177 healthy controls are genotyped by PCR-RFLP method for the SNP rs2476601 (A/G) of PTPN22 gene. Polymorphic region was amplified by PCR and digested with Xcm I enzyme. Results. Detected frequencies of heterozygous genotype (AG) were 5.1% (9/177) in control group and 3.8% (7/181) in TA group (P = 0.61, odds ratio: 0.75, 95% CI: 0.3, 2.0). No association with angiographic type, vascular involvement or prognosis of TA was observed either. Conclusion. The distribution of PTPN22 polymorphism did not reveal any association with TA in Turkey. © The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved

Whole Exome Sequencing Identifies Rare Protein-Coding Variants in Behçet's Disease

Behçet's disease (BD) is a systemic inflammatory disease with an incompletely understood etiology. Despite the identification of multiple common genetic variants associated with BD, rare genetic variants have been less explored. We undertook this study to investigate the role of rare variants in BD by performing whole exome sequencing in BD patients of European descent. METHODS: Whole exome sequencing was performed in a discovery set comprising 14 German BD patients of European descent. For replication and validation, Sanger sequencing and Sequenom genotyping were performed in the discovery set and in 2 additional independent sets of 49 German BD patients and 129 Italian BD patients of European descent. Genetic association analysis was then performed in BD patients and 503 controls of European descent. Functional effects of associated genetic variants were assessed using bioinformatic approaches. RESULTS: Using whole exome sequencing, we identified 77 rare variants (in 74 genes) with predicted protein-damaging effects in BD. These variants were genotyped in 2 additional patient sets and then analyzed to reveal significant associations with BD at 2 genetic variants detected in all 3 patient sets that remained significant after Bonferroni correction. We detected genetic association between BD and LIMK2 (rs149034313), involved in regulating cytoskeletal reorganization, and between BD and NEIL1 (rs5745908), involved in base excision DNA repair (P = 3.22 × 10(-4) and P = 5.16 × 10(-4) , respectively). The LIMK2 association is a missense variant with predicted protein damage that may influence functional interactions with proteins involved in cytoskeletal regulation by Rho GTPase, inflammation mediated by chemokine and cytokine signaling pathways, T cell activation, and angiogenesis (Bonferroni-corrected P = 5.63 × 10(-14) , P = 7.29 × 10(-6) , P = 1.15 × 10(-5) , and P = 6.40 × 10(-3) , respectively). The genetic association in NEIL1 is a predicted splice donor variant that may introduce a deleterious intron retention and result in a noncoding transcript variant. CONCLUSION: We used whole exome sequencing in BD for the first time and identified 2 rare putative protein-damaging genetic variants associated with this disease. These genetic variants might influence cytoskeletal regulation and DNA repair mechanisms in BD and might provide further insight into increased leukocyte tissue infiltration and the role of oxidative stress in BD

Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy.

Giant cell arteritis (GCA) and Takayasu’s arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus

Corrigendum: Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy.

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P\u2009=\u20097.54E-07; ORGCA\u2009=\u20091.19, ORTAK\u2009=\u20091.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA\u2009=\u20095.52E-04, ORGCA\u2009=\u20091.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus

Early

Arthritis Rheum. 2004 Dec;50(12):3934-40. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gül A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R. Université Catholique de Louvain, Brussels, Belgium. [email protected] Abstract OBJECTIVE: In the Euro-Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high-dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low-dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors. METHODS: Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan-Meier method. RESULTS: After a median followup of 73 months, there was no significant difference in the cumulative probability of end-stage renal disease or doubling of the serum creatinine level in patients who received the low-dose IV CYC regimen versus those who received the high-dose regimen. At long-term followup, 18 patients (8 receiving low-dose and 10 receiving high-dose treatment) had developed permanent renal impairment and were classified as having poor long-term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/24 hours) was the best predictor of good long-term renal outcome. CONCLUSION: Long-term followup of patients from the ELNT confirms that, in lupus nephritis, a remission-inducing regimen of low-dose IV CYC followed by AZA achieves clinical results comparable with those obtained with a high-dose regimen. Early response to therapy is predictive of good long-term renal outcome. PMID: 15593207 [PubMed - indexed for MEDLINE

Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behcet's Disease

Objective. Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet’s disease in a diverse multiethnic population.Methods. A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray- 24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed.Results. We identified 2 novel genetic susceptibility loci for Behçet’s disease, including a risk locus in IFNGR1(rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10−9) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10−8). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide- stimulated monocytes. In addition, our results replicated the association (P 30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10−5), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated.Conclusion. We performed the largest genetic association study in Behçet’s disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries