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Expression in Systemic Lupus Erythematosus Patients and Healthy Controls1
,*
* Kennedy Institute of Rheumatology and
Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
TCR
(CD247) functions as an amplification module in the TCR signaling cascade and is essential for assembly and surface expression of the TCR/CD3 complex. The TCR-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCR expression is a cause or a consequence of chronic inflammatory responses. We have addressed this question by adopting a combined genetic and functional approach. We analyzed TCR protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCR expression in healthy individuals. The variation in TCR expression was associated with polymorphisms in the CD3Z 3'-untranslated region (UTR) in SLE patients and healthy controls. Detailed mapping of the 3'-UTR revealed that the minor alleles of two single nucleotide polymorphisms (SNPs) in strong disequilibrium (rs1052230 and rs1052231) were the causal variants associated with low TCR expression (p = 0.015). Using allelic imbalance analysis, the minor alleles of these 3'-UTR SNPs were associated with one-third of the level of mRNA compared with the major allele. A family-based association analysis showed that the haplotype carrying the low-expression variants predisposes to SLE (p = 0.033). This suggests that a genetically determined reduction in TCR expression has functional consequences manifested by systemic autoimmunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by funding from an European Union Framework 6 Integrated Project (AutoCure), the Wellcome Trust United Kingdom, the Arthritis Research Campaign, and a Clinical Research Fellowship awarded to C.L.G. by the Trustees of the Kennedy Institute of Rheumatology.
2 C.L.G. and A.I.R. contributed equally to this manuscript.
3 Address correspondence and reprint requests to Dr. Claire L. Gorman, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, U.K. E-mail address: c.gorman{at}imperial.ac.uk
4 Senior authors A.P.C. and T.J.V. contributed equally to this manuscript.
5 Abbreviations used in this paper: 3'-UTR, 3' untranslated region; ARE, adenine-uridine-rich element; Elf-1, E-74-like factor; LD, linkage disequilibrium; MFI, mean fluorescence intensity; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium test.
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