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    ABSTRACT: Objective: We performed whole-blood transcriptomic profiling for patients with rheumatoid arthritis (RA) who received rituximab (RTX). We aimed to identify a molecular signature that could predict the clinical response to RTX and transcriptomic changes after RTX therapy.Methods: We performed a microarray assay of the whole human genome with RNA from a peripheral blood sample taken before the first RTX cycle from 68 patients included in the SMART study (24 EULAR non-responders and 44 responders at week 24). The transcriptomic profile was also assessed 24 weeks after the first RTX administration, and Ingenuity Interactive Pathways Analysis (IPA) was used to identify molecular pathways modified by RTX therapy according to the clinical response. Quantitative PCR was performed to confirm microarray results.Results: At baseline, 198 genes showed significant differential expression between RTX responders and non-responders. This molecular signature could be reduced to 143 genes, which allowed for classifying 89% of patients by EULAR response status at week 24, with 100% classification of non-responders. The signature for response featured up-regulation of inflammatory genes centered on NF-kB, including interleukin 33 and signal transducer and activator of transcript 5A, and down-regulation of the interferon pathway. As expected, at week 24 post-RTX therapy, genes involved in B-cell development and functions were the strongest downregulated genes without any difference between both groups.Conclusion: Whole-blood transcriptomic analyses may accurately identify patients with RA who will not respond to RTX therapy and open new perspectives to tailor RA management. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 04/2014;
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    ABSTRACT: Abstract The Thr allele at the Thr946Ala non-synonymous single-nucleotide polymorphism (nsSNP) in the IFIH1 gene confers risk for type 1 diabetes (T1D). IFIH1 binds viral double-stranded RNA (dsRNA), inducing a type I interferon (IFN) response. Reports of this nsSNP's role in IFIH1 expression regulation have produced conflicting results and a study evaluating transfected Thr946Ala protein alleles in an artificial system overexpressing IFIH1 shows that the SNP does not affect IFH1 function. In this study, we examine the effects of the Thr946Ala polymorphism on IFN-α response in a cell line that endogenously expresses physiological levels of IFIH1. Eleven lymphoblastoid cell lines (LCLs) homozygous for the major predisposing allele (Thr/Thr) and 6 LCLs homozygous for the minor protective allele (Ala/Ala) were electroporated with the viral dsRNA mimic, poly I:C, in three independent experiments. Media were collected 24 hours later and measured for IFN-α production by ELISA. Basal IFN response is minimal in mock-transfected cells from both genotypes and increases by about 8-fold in cells treated with poly I:C. LCLs with the Ala/Ala genotype have slightly higher IFN-α levels than their Thr/Thr counterparts but this did not reach statistical significance because of the large variability of the IFN response, due mostly to two high outliers (biological, not technical). A larger sample size would be needed to determine whether the Thr946Ala SNP affects the poly I:C-driven IFN-α response. Additionally, the possibility that this nsSNP recognizes viral dsRNA specificities cannot be ruled out. Thus, the mechanism of the observed association of this SNP with T1D remains to be determined.
    Autoimmunity 10/2013; · 2.77 Impact Factor
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    ABSTRACT: Identification of genetic variants that influence bipolar I disorder (BPD-I) through genome-wide association (GWA) studies are limited in Asian populations. The current study aimed to identify novel common variants for BPD-I in an ethnically homogeneous Taiwanese sample using a multi-stage GWA study design. At the discovery stage, 200 BPD-I patients and 200 controls combined to form 16 pools were genotyped with 1 million markers. Utilizing a newly developed rank-based method, top-ranked markers were selected. After validation with individual genotyping, a fine-mapping association study was conducted to identify associated loci using 240 patients and 240 controls. At the last stage, independent samples were collected (351 cases and 341 controls) for replication. Among the top-ranked markers from the discovery stage, eight genes and 15 individual SNPs were evaluated in the fine-mapping stage. At this stage, rs7619173, which is not in a gene coding region, showed the most significant association (P=2*10(-5)) with BPD-I. Four genes had empirical p-values <0.05, including KCNH7 (P=0.0047), MYST4 (P=0.0047), NRXN3 (P=0.0095), and SEMA3D (P=0.037). For markers genotyped in replication samples, rs7619173 exhibited a significant association (Pcombined=2*10(-4)) after multiple testing correction, while markers rs11001178 (MYST4) and rs2217887 (NRXN3) showed weak associations (Pcombined=0.02) with BPD-I. A multi-stage GWA design has the potential to uncover the underlying pathogenesis of a complex trait. Findings in the present study highlight three loci that warrant further investigation for bipolar.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2014; · 3.55 Impact Factor