ABSTRACT
GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differentiation and have been previously connected to immune-mediated disorders in animal studies. GIMAP4 is believed to contribute to the Th cell subtype-driven immunological balance via its role in T cell survival. GIMAP5 has a key role in BB-DR rat and NOD mouse lymphopenia. To elucidate GIMAP4 and GIMAP5 function and role in human immunity, we conducted a study combining genetic association in different immunological diseases and complementing functional analyses. Single nucleotide polymorphisms tagging the GIMAP haplotype variation were genotyped in Finnish type 1 diabetes (T1D) families and in a prospective Swedish asthma and allergic sensitization birth cohort. Initially, GIMAP5 rs6965571 was associated with risk for asthma and allergic sensitization (odds ratio [OR] 3.74, p = 0.00072, and OR 2.70, p = 0.0063, respectively) and protection from T1D (OR 0.64, p = 0.0058); GIMAP4 rs13222905 was associated with asthma (OR 1.28, p = 0.035) and allergic sensitization (OR 1.27, p = 0.0068). However, after false discovery rate correction for multiple testing, only the associations of GIMAP4 with allergic sensitization and GIMAP5 with asthma remained significant. In addition, transcription factor binding sites surrounding the associated loci were predicted. A gene-gene interaction in the T1D data were observed between the IL2RA rs2104286 and GIMAP4 rs9640279 (OR 1.52, p = 0.0064) and indicated between INS rs689 and GIMAP5 rs2286899. The follow-up functional analyses revealed lower IL-2RA expression upon GIMAP4 knockdown and an effect of GIMAP5 rs2286899 genotype on protein expression. Thus, the potential role of GIMAP4 and GIMAP5 as modifiers of immune-mediated diseases cannot be discarded.
Subject(s)
Asthma/genetics , Diabetes Mellitus, Type 1/genetics , GTP-Binding Proteins/genetics , Hypersensitivity/genetics , 3' Untranslated Regions , Adolescent , Adult , Alleles , Animals , Asthma/immunology , Binding Sites , Cell Line , Cell Membrane/metabolism , Child , Child, Preschool , Datasets as Topic , Diabetes Mellitus, Type 1/immunology , Epistasis, Genetic , Female , Finland , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Genotype , Geography , Humans , Hypersensitivity/immunology , Infant , Interleukin-2 Receptor alpha Subunit/metabolism , Linkage Disequilibrium , Male , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Although GTPase of the immunity-associated protein (GIMAP) family are known to be most highly expressed in the cells of the immune system, their function and role remain still poorly characterized. Small GTPases in general are known to be involved in many cellular processes in a cell type-specific manner and to contribute to specific differentiation processes. Among GIMAP family, GIMAP4 is the only member reported to have true GTPase activity, and its transcription is found to be differentially regulated during early human CD4(+) T helper (Th) lymphocyte differentiation. GIMAP4 has been previously connected mainly with T- and B-cell development and survival and T-cell apoptosis. Here we show GIMAP4 to be localized into cytoskeletal elements and with the component of the trans golgi network, which suggests it to have a function in cellular transport processes. We demonstrate that depletion of GIMAP4 with RNAi results in downregulation of endoplasmic reticulum localizing chaperone VMA21. Most importantly, we discovered that GIMAP4 regulates secretion of cytokines in early differentiating human CD4(+) Th lymphocytes and in particular the secretion of interferon-γ also affecting its downstream targets.