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GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy This information is current as Mirkka T. Heinonen, Antti-Pekka Laine, Cilla Söderhäll, of September 26, 2021. Olena Gruzieva, Sini Rautio, Erik Melén, Göran Pershagen, Harri J. Lähdesmäki, Mikael Knip, Jorma Ilonen, Tiina A. Henttinen, Juha Kere, Riitta Lahesmaa and The Finnish Pediatric Diabetes Registry J Immunol 2015; 194:5885-5894; Prepublished online 11 Downloaded from May 2015; doi: 10.4049/jimmunol.1500016 http://www.jimmunol.org/content/194/12/5885 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/05/09/jimmunol.150001 Material 6.DCSupplemental References This article cites 50 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/194/12/5885.full#ref-list-1 Why The JI? Submit online. by guest on September 26, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology GIMAP GTPase Family Genes: Potential Modifiers in Autoimmune Diabetes, Asthma, and Allergy Mirkka T. Heinonen,*,†,‡,1 Antti-Pekka Laine,x,1 Cilla So¨derha¨ll,{ Olena Gruzieva,‖ Sini Rautio,# Erik Mele´n,‖,** Go¨ran Pershagen,‖ Harri J. La¨hdesma¨ki,*,‖ Mikael Knip,††,‡‡,xx,{{ Jorma Ilonen,x,‖‖,2 Tiina A. Henttinen,†,2 Juha Kere,{,##,2 Riitta Lahesmaa,*,2 and The Finnish Pediatric Diabetes Registry3 GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differen- tiation 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 Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2015, 194: 5885–5894. TPase of the immunity-associated protein (GIMAP) family shown GIMAPs to interact with known apoptosis regulators and proteins are expressed most extensively in the immune have a role in the differentiation, survival, and apoptosis of T cells G system and are differentially regulated during early human and some other cell types (7–9). by guest on September 26, 2021 Th cell differentiation (1), highly expressed in the course of Th1 Th cells represent an integral component of the immune system differentiation, and less so during Th2 differentiation. Although and are thus intrinsic to immune-mediated diseases. Activated naive GIMAPs have been shown to act as lymphocyte signaling molecules CD4+ Th cells differentiate into distinct subtypes in a balanced and (reviewed by File´n and Lahesmaa [2]), the function of these recently regulated manner to mediate immune responses. A disruption in this identified putative GTPases remains poorly characterized (3–6). balance can result in immune-mediated disorders. Examples of this Only a few studies focusing on the function of GIMAPs in humans are illustrated in type 1 diabetes (T1D), where it is proposed that have been conducted to date. Previous animal studies have clearly T cell–mediated damage of the b cells is associated with a high *Turku Centre of Biotechnology, University of Turku and A˚ bo Akademi University, BAMSE study was supported by the Swedish Research Council for Environment, 20520 Turku, Finland; †Department of Biology, University of Turku, 20014 Turku, Fin- Agricultural Sciences and Spatial Planning, the Swedish Heart-Lung Foundation, the land; ‡Turku Doctoral Programme of Molecular Medicine, University of Turku, 20520 Stockholm County Council Anna Lindh Foundation, and the Strategic Research Area Turku Finland; xImmunogenetics Laboratory, University of Turku, 20520 Turku, Epidemiology Program at Karolinska Institutet. Finland; {Department of Bioscience and Nutrition and Center for Innovative Medicine, ‖ Address correspondence and reprint requests to Prof. Riitta Lahesmaa, Turku Centre Karolinska Institutet, 141 83 Huddinge, Stockholm, Sweden; Institute of Environmental of Biotechnology, University of Turku and A˚ bo Akademi University, Tykisto¨katu 6A, Medicine, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden; #Department 20520 Turku, Finland. E-mail address: riitta.lahesmaa@btk.fi of Information and Computer Science, Aalto University, 02150 Espoo, Finland; **Karolinska University Hospital, Astrid Lindgren Children’s Hospital, 171 76 Solna, The online version of this article contains supplemental material. Stockholm, Sweden; ††Children’s Hospital, University of Helsinki and Helsinki Univer- Abbreviations used in this article: ActD, actinomyosin D; BAMSE, Children, Al- sity Hospital, 00029 Helsinki, Finland; ‡‡Research Programs Unit, Diabetes and Obesity, xx lergy, Milieu, Stockholm, Epidemiology; CEU, Utah residents of northern and west- University of Helsinki, 00290 Helsinki, Finland; Department of Pediatrics, Tampere {{ ern European ancestry (CEPH); Ct, cycle threshold; FDR, false discovery rate; University Hospital, 33521 Tampere, Finland; Folkha¨lsan Research Institute, 00290 ‖‖ FOXO1, forkhead box O1, transcription factor; FPDR, Finnish Pediatric Diabetes Helsinki, Finland; Department of Clinical Microbiology, University of Eastern Finland, Registry; FPDRNF, nuclear families from the Finnish Pediatric Diabetes Registry; 70211 Kuopio, Finland; and ##Molecular Neurology Research Program, University of GIMAP, GTPase of the immunity-associated protein; GWAS, genome-wide associ- Helsinki and Folkha¨lsan Institute of Genetics, 00290 Helsinki, Finland ation study; HWE, Hardy–Weinberg equilibrium; INS, insulin gene; LD, linkage 1M.T.H. and A.-P.L. contributed equally to this work. disequilibrium; luc, luciferase; NE, Northeast; OR, odds ratio; PTPN22, protein tyrosine phosphatase, nonreceptor type 22 gene; r2, square of the sample correlation 2J.I., T.A.H., J.K., and R.L. contributed equally to this work. coefficient; siGIMAP, GIMAP-specific small interfering RNA; SNP, single nucleo- 3All authors and their affiliations appear at the end of this article. tide polymorphism; SW, Southwest; T1D, type 1 diabetes; Treg, T regulatory cell; UTR, untranslated region. Received for publication January 7, 2015. Accepted for publication March 30, 2015. This article is distributed under The American Association of Immunologists, Inc., This work was supported by the Academy of Finland (Centre of Excellence in Reuse Terms and Conditions for Author Choice articles. Molecular Systems Immunology and Physiology Research, 2012–2017, Decision 250114, and Grants 140019 and 255808), the Juvenile Diabetes Research Founda- Ó tion, The Sigrid Juselius Foundation, and a Turku University Hospital grant. The Copyright 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500016 5886 GIMAP GENES AS IMMUNE-MEDIATED DISEASE MODIFIERS Th1/Th2 ratio (10, 11), and in asthma, where the ratio is believed to support GIMAP4 and GIMAP5 having a role as putative modifiers of be the opposite (12). In a recent genome-wide association study immune-mediated disorders, possiblyactinginIL-2andforkhead (GWAS) on patients with asthma, Li et al. (13) suggested that the box O1, transcription factor (FOXO1)/insulin signaling, respectively. single nucleotide polymorphisms (SNPs)