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

Abstract

In a recent study of Multiple Sclerosis (MS), we observed additive effects and epistatic interactions between variants of four genes that converge to induce T cell hyper-activity 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 datasets, epistatic and additive effects were observed using 1,423 multiplex families from the Type 1 Diabetes Genetic Consortium dataset. The IL2RA and IL7RA variants had univariate association in MS and T1D, while 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.