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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CTLA-4 Antigen / genetics*
  • CTLA-4 Antigen / immunology
  • Datasets as Topic
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Epistasis, Genetic* / immunology
  • Family*
  • Female
  • Genetic Variation / immunology*
  • Humans
  • Interleukin-2 Receptor alpha Subunit / genetics*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Male
  • N-Acetylglucosaminyltransferases / genetics*
  • N-Acetylglucosaminyltransferases / immunology
  • Receptors, Interleukin-7 / genetics*
  • Receptors, Interleukin-7 / immunology


  • CTLA-4 Antigen
  • CTLA4 protein, human
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Interleukin-7
  • MGAT1 protein, human
  • N-Acetylglucosaminyltransferases