title: Family studies of type 1 diabetes reveal additive and epistatic effects between MGAT1 and three other polymorphisms.
abstract: In a recent study on multiple sclerosis (MS), we observed additive effects and epistatic interactions between variants of four genes that converge to induce T-cell hyperactivity by altering Asn-(N)-linked protein glycosylation: namely, the Golgi enzyme MGAT1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), interleukin-2 receptor-α (IL2RA) and interleukin-7 receptor-α (IL7RA). As the CTLA-4, IL2RA and IL7RA variants are associated with type 1 diabetes (T1D), we examined for joint effects in T1D. Employing a novel conditional logistic regression for family-based data sets, epistatic and additive effects were observed using 1423 multiplex families from the Type 1 Diabetes Genetic Consortium data set. The IL2RA and IL7RA variants had univariate association in MS and T1D, whereas the MGAT1 and CTLA-4 variants associated with only MS or T1D, respectively. However, similar to MS, the MGAT1 variant haplotype interacted with CTLA4 (P=0.03), and a combination of IL2RA and IL7RA (P=0.01). The joint effects of MGAT1, CTLA4, IL2RA, IL7RA and the two interactions using a multiple conditional logistic regression were statistically highly significant (P<5 × 10(-10)). The MGAT1-CTLA-4 interaction was replicated (P=0.01) in 179 trio families from the Genetics of Kidneys in Diabetes study. These data are consistent with defective N-glycosylation of T cells contributing to T1D pathogenesis.
authors.affiliation: Department of Statistics, University of California, Irvine, CA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.affiliation: 1] Department of Neurology, University of California, Irvine, CA, USA [2] Institute for Immunology, University of California, Irvine, CA, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Mkhikian
authors.affiliation: Department of Microbiology & Molecular Genetics, University of California, Irvine, CA, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Zhou
authors.affiliation: Department of Neurology, University of California, Irvine, CA, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Newton
authors.affiliation: 1] Department of Neurology, University of California, Irvine, CA, USA [2] Institute for Immunology, University of California, Irvine, CA, USA [3] Department of Microbiology & Molecular Genetics, University of California, Irvine, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Demetriou
mesh_terms: D060908:CTLA-4 Antigen / Q000235:genetics* / Q000276:immunology; D066264:Datasets as Topic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D004843:Epistasis, Genetic / Q000276:immunology; D005190:Family; D005260:Female; D014644:Genetic Variation / Q000276:immunology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D020395:Receptors, Interleukin-7; C561128:MGAT1 protein, human; D017351:N-Acetylglucosaminyltransferases