Hypomorphic MGAT5 polymorphisms promote multiple sclerosis cooperatively with MGAT1 and interleukin-2 and 7 receptor variants.
Deficiency of the Golgi N-glycan branching enzyme Mgat5 in mice promotes T cell hyperactivity, endocytosis of CTLA-4 and autoimmunity, including a spontaneous multiple sclerosis (MS)-like disease. Multiple genetic and environmental MS risk factors lower N-glycan branching in T cells. These include variants in interleukin-2 receptor-α (IL2RA), interleukin-7 receptor-α (IL7RA), and MGAT1, a Golgi branching enzyme upstream of MGAT5, as well as vitamin D3 deficiency and Golgi substrate metabolism. 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 IL7RA MS risk variants (p=1.76×10(-9), OR=0.67-1.83, n=3,518).
Department of Neurology, University of California, Irvine, CA 92869, USA.
Carey F
CF
Li
Raymond W
RW
Zhou
Haik
H
Mkhikian
Barbara L
BL
Newton
Zhaoxia
Z
Yu
Michael
M
Demetriou
D000328:Adult; D060908:CTLA-4 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics*; D020395:Receptors, Interleukin-7 / Q000235:genetics*; D012307:Risk Factors; D013601:T-Lymphocytes / Q000378:metabolism; D055815:Young Adult
D060908:CTLA-4 Antigen; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D005700:Galactosyltransferases; D017351:N-Acetylglucosaminyltransferases