GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy

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.

TAL1-mediated epigenetic modifications down-regulate the expression of GIMAP family in non-small cell lung cancer

“…The hGIMAPs genes encoding these small GTPases belong to a family that is evolutionarily conserved in Arabidopsis, mice, rats and humans. These have been postulated to regulate apoptosis, particularly in the case of diseases such as cancer, diabetes and infection [7,12]. In this study, we used the TCGA and GEO databases to report down-regulation of hGIMAPs in NLCSC and analyzed that low expression of all seven GIMAP genes was associated with poor prognosis, which is consistent with shiao et al [13].…”

“…Consistent with this, GIMAP1 is essential for the survival of naive and activated B cells in vivo [6]. GIMAP 4 participates in Th cell subset-driven immune balance through its role in T cell survival [7]. Deletion of GIMAP5 promotes the development of pathogenic CD4 + T cells and the development of allergic airway disease [8].…”

Multi-species protein similarity clustering reveals novel expanded immune gene families in the eastern oyster Crassostrea virginica

“…A novel finding of this research is the high and unprecedented diversity of GIMAP transcripts (101) seen in the transcriptomes of eastern oysters in response to bacterial challenge, which is remarkable considering that GIMAP genes are completely absent in many vertebrate and invertebrate species. GTPase of the immunity-associated proteins (GIMAPs), also known as immune-associated-nucleotide-binding proteins (IANs), are G proteins with one or two GTPase domain (Ciucci & Bosselut 2014;Heinonen et al 2015). These proteins were first identified in plants as responsible for disease resistance to bacterial infection (Reuber & Ausubel 1996).…”

Survival of mature T cells in the periphery is intrinsically dependent on GIMAP1 in mice

“…In addition, GIMAP expression is reduced in regulatory T cells of patients with type I diabetes , and a single nucleotide polymorphism in the polyadenylation signal of human Gimap5 is associated with IA‐2 autoantibody formation in patients with type I diabetes and predisposes individuals to systemic lupus erythematosus . Similarly, gene association studies have implicated GIMAPs in other autoimmune diseases such as Behçet's disease and for asthma and allergy sensitization . Yet, despite these associations, we still know relatively little about GIMAPs and how they function.…”