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    ABSTRACT: The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.Genes and Immunity advance online publication, 28 March 2013; doi:10.1038/gene.2013.9.
    Genes and immunity 03/2013; · 4.22 Impact Factor
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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: The IFIH1 gene is a key factor connecting environmental and genetic factors in the pathogenesis of immune-related diseases. We aimed to investigate whether it has effects on psoriasis, chronic periodontitis and skin test-positive penicillin allergy and to confirm whether these diseases have shared molecular mechanisms originating from shared genetics. Two common variants in IFIH1 were genotyped in 561 patients with psoriasis, 421 patients with chronic periodontitis, 175 patients with skin test-positive penicillin allergy and 1100 shared controls. Then, case-control study was used to analyse the association between IFIH1 and the three diseases. The allele distributions of rs1990760 and rs3747517 in the Chinese population are much different from the European population. The A allele of rs1990760 (OR = 1.30, P = 5.4 × 10(-3)) and A-G (rs1990760/rs3747517) haplotype (OR = 1.31, P = 3.8 × 10(-3)) were highly associated with the risk of psoriasis. However, the A allele of rs1990760 (OR = 0.73, P = 7.8 × 10(-3)) and A-G haplotype (OR = 0.71, P = 4.5 × 10(-3)) were identified as protective factors for chronic periodontitis. IFIH1 affects several immune-related diseases, including psoriasis and chronic periodontitis, and provides a molecular link between genetic susceptibility, viral infections and immune-related diseases. Moreover, we also confirm the hypothesis that shared molecular mechanisms from common genetic variants contribute to a spectrum of immune-related diseases.
    International Journal of Immunogenetics 12/2011; 39(2):137-43. · 1.36 Impact Factor