title: 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.
authors.affiliation: Turku Centre of Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Department of Biology, University of Turku, 20014 Turku, Finland; Turku Doctoral Programme of Molecular Medicine, University of Turku, 20520 Turku Finland;
authors.forename: Mirkka T
authors.initials: MT
authors.lastname: Heinonen
authors.affiliation: Immunogenetics Laboratory, University of Turku, 20520 Turku, Finland;
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Laine
authors.affiliation: Department of Bioscience and Nutrition and Center for Innovative Medicine, Karolinska Institutet, 141 83 Huddinge, Stockholm, Sweden;
authors.forename: Cilla
authors.initials: C
authors.lastname: Söderhäll
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden;
authors.forename: Olena
authors.initials: O
authors.lastname: Gruzieva
authors.affiliation: Department of Information and Computer Science, Aalto University, 02150 Espoo, Finland;
authors.forename: Sini
authors.initials: S
authors.lastname: Rautio
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden; Karolinska University Hospital, Astrid Lindgren Children's Hospital, 171 76 Solna, Stockholm, Sweden;
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden;
authors.forename: Göran
authors.initials: G
authors.lastname: Pershagen
authors.affiliation: Turku Centre of Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Environmental Medicine, Karolinska Institutet, 171 65 Solna, Stockholm, Sweden;
authors.forename: Harri J
authors.initials: HJ
authors.lastname: Lähdesmäki
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland; Research Programs Unit, Diabetes and Obesity, University of Helsinki, 00290 Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, 33521 Tampere, Finland; Folkhälsan Research Institute, 00290 Helsinki, Finland;
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Immunogenetics Laboratory, University of Turku, 20520 Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, 70211 Kuopio, Finland; and.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Department of Biology, University of Turku, 20014 Turku, Finland;
authors.forename: Tiina A
authors.initials: TA
authors.lastname: Henttinen
authors.affiliation: Department of Bioscience and Nutrition and Center for Innovative Medicine, Karolinska Institutet, 141 83 Huddinge, Stockholm, Sweden; Molecular Neurology Research Program, University of Helsinki and Folkhälsan Institute of Genetics, 00290 Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Turku Centre of Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland; riitta.lahesmaa@btk.fi.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D066264:Datasets as Topic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D004843:Epistasis, Genetic; D005260:Female; D005387:Finland; D019204:GTP-Binding Proteins / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005843:Geography; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics* / Q000276:immunology; D007223:Infant; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C485688:GIMAP4 protein, human; C484030:GIMAP5 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D019204:GTP-Binding Proteins