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Genes Immun. 2014 Apr;15(4):218-23. doi: 10.1038/gene.2014.7. Epub 2014 Feb 27.

Family studies of type 1 diabetes reveal additive and epistatic effects between MGAT1 and three other polymorphisms.

Author information

1
Department of Statistics, University of California, Irvine, CA, USA.
2
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.
4
Department of Neurology, University of California, Irvine, CA, USA.
5
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.

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.

PMID:
24572742
PMCID:
PMC4047175
DOI:
10.1038/gene.2014.7
[Indexed for MEDLINE]
Free PMC Article

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