Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Contains fulltext : 97006.pdf (publisher's version ) (Open Access)The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc

Sympathetic denervation in patients with ischemic cardiomyopathy and risk on ventricular tachy-arrhythmias. A pilot study

BACKGROUND: Patients with ischemic cardiomyopathy (ICM) are at risk for ventricular arrhythmias and are protected by an implantable cardioverter defibrillator (ICD). Visualization of cardiac sympathetic innervation may play an additional role to left ventricular ejection fraction (LVEF) in identifying those patients who will benefit from ICD therapy. The purpose of this study was to detect the role of sympathetic denervation in the genesis of ventricular arrhythmias in ICM patients. METHODS: Twenty patients with ICM and LVEF RESULTS: Mean age was 63 +/- 7.5 years. Mean global retention of [C-11]-mHED was 0.055 +/- 0,012 min(-1), and was not different between the two patient groups: 0.056 +/- 0.011 min(-1) vs. 0.054 +/- 0.013 min(-1) for group A vs. group B, respectively. During follow-up, seven patients developed ventricular arrhythmias, and four patients died. No difference in [C-11]-mHED retention was found between patients with and without ventricular arrhythmia during follow-up. However, size of denervated area was larger in patients who died during follow-up: 10 +/- 1 segments vs. 6 +/- 2 segments, P=0.002. CONCLUSIONS: Cardiac sympathetic innervation is impaired in patients with ischemic cardiomyopathy. All-cause mortality occurred in those patients with large areas of [C-11]-mHED defect

[F-18]FLT-PET and [F-18]FDG-PET in the evaluation of radiotherapy for laryngeal cancer

The evaluation of response to radiotherapy in patients with laryngeal cancer is a challenge because of the difficulty to differentiate between post-therapy changes and recurrent or residual tumor. Positron emission tomography is a non-invasive imaging tool that may be helpful in this differentiation. In this study, [F-18]-fluoro-3'-deoxy-L-thymidine ([F-18]FLT), a proliferation tracer is compared with 2-[F-18]-fluoro-2-deoxy-D-glucose ([F-18]FDG). Patients with primary laryngeal cancer, scheduled to undergo radiotherapy were included in this study. Patients underwent both [F-18]FLT-PET and [F-18]FDG-PET shortly before radiotherapy. Ten patients underwent [F-18]FLT-PET and [F-18]FDG-PET 2-3 months after radiotherapy. Scans were analyzed visually for areas of increased tracer uptake. The standardized uptake value (SUV) was measured as a semi-quantitative value of tracer uptake. Fourteen patients, all male, were included in this study. Both [F-18]FLT-PET and [F-18]FDG-PET showed increased tracer uptake in 12 out of 14 patients (86%). [F-18]FDG uptake was significantly higher than [F-18]FLT uptake (SUVmax: 4.5 vs. 2.4 (P = 0.002); SUVmean: 3.4 vs. 1.9 (P = 0.002)). After radiotherapy, 3 patients had histologically proven residual or recurrent laryngeal cancer. [F-18]FDG was true positive in 2 out of 3 patients, whereas [F-18]FLT showed increased tracer uptake in only one. Of the remaining 7 patients, [F-18]FLT was true negative in all, whereas [F-18]FDG showed increased uptake in one (false positive). [F-18]FLT-PET is feasible in visualizing laryngeal cancer and its evaluation of treatment. The overall uptake of this tracer is significantly lower as compared with [F-18]FDG, but tumor to background ratios are comparable. (C) 2009 Published by Elsevier Ltd

Perception of burden experienced during diagnostic tests by melanoma patients with lymph node metastases

Melanoma patients with lymph node metastases have to deal with diagnostic tests to exclude the presence of distant metastases; results of the tests could have major implications for their prognosis and treatment There are, however, few studies concerning the patients' psychological issues and perception of diagnostic tests. The aim of this study was to describe the burden of diagnostic tests [radiograph, computed tomography (CT) and positron emission tomography (PET)] experienced by melanoma patients with lymph node metastases. Patients were asked to complete a questionnaire concerning satisfaction and burden experienced during the diagnostic tests. The levels of embarrassment, discomfort and anxiety for the different tests, as well as total scores for each burden were calculated. Logistic regression was used to examine factors associated with the degree of experienced burden. Fifty-nine of the 68 patients completed the questionnaire and the response rate was 87%. The overall mean scores on satisfaction and quality of life were high. More than half of the patients experienced no burden during PET, 65% no burden during computed tomography and 80% no burden during chest radiograph. Patients experienced significantly more discomfort during the PET scan than during the CT (P=0.003). Less burden was experienced (in univariate analysis) by patients who were more satisfied. The overall experienced burden by patients is low and should therefore not interfere with primary choice for a diagnostic test based on accuracy, costs and percentage of patients upstaged. Attention should be paid in explaining the procedure and answering questions of the patients to reduce burden. Melanoma Res 19:36-41 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins