title: Polymorphisms in the CD3Z gene influence TCRzeta expression in systemic lupus erythematosus patients and healthy controls.
abstract: TCRzeta (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 TCRzeta-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCRzeta 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 TCRzeta protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCRzeta expression in healthy individuals. The variation in TCRzeta 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 TCRzeta 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 TCRzeta expression has functional consequences manifested by systemic autoimmunity.
authors.affiliation: Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, UK. c.gorman@imperial.ac.uk
authors.forename: Claire L
authors.initials: CL
authors.lastname: Gorman
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Russell
authors.forename: Zhuoli
authors.initials: Z
authors.lastname: Zhang
authors.forename: Deborah
authors.initials: D
authors.lastname: Cunninghame Graham
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cope
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D022981:Allelic Imbalance; D015551:Autoimmunity / Q000235:genetics*; D001483:Base Sequence; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D008565:Membrane Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain