Here we describe linked intronic variants of MGAT5 that are associated with reduced N-glycan branching, CTLA-4 surface expression and MS (p=5.79×10(-9), n=7,741), the latter additive with the MGAT1, IL2RA and IL7RAMS risk variants (p=1.76×10(-9), OR=0.67-1.83, n=3,518).
CD127 expression is lower in more differentiated cells, such as Th1s, which can be elevated in MS. A higher proportion of these two abundant cell types in peripheral blood could be the basis for the observed reduction in CD127 mRNA.
For example, nucleotide variation in the interleukin 7 receptor (IL7RA), the interleukin 2 receptor (IL2RA), the CD58 and the c-type lectin domain family 16 member A (CLEC16A) genes has been consistently associated with MS in several populations.
Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17.
A central role for T cells in MS is supported by mouse models, association of the major histocompatibility complex region, and association of critical T cell growth regulator genes such as interleukin-2 receptor (IL-2RA) and interleukin-7 receptor (IL-7RA).
The C allele of a single nucleotide polymorphism (SNP), rs6897932, located in the interleukin-7 receptor alpha chain (IL7RA) was recently found to be associated with multiple sclerosis and Type I diabetes.
Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055).
A number of studies with compelling evidence have provided correlation between single nucleotide polymorphisms in interleukin-7 receptor alpha and multiple sclerosis (MS) in several populations.
The levels of sIL-7Rα increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Rα could result in a higher mIL-7Rα to soluble IL-7Rα ratio.
IL7R gene polymorphisms which are associated with several autoimmune diseases have also been implicated as a genetic factor for MS following genome-wide association studies.
The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R.
Together these results confirm involvement of polymorphisms in the IL7RA and IL2RA genes in MS pathogenesis and suggest that IL7RA variation may primarily affect chronic disease courses.
A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS.