Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers

Glycosylation of immunoglobulin g (igg) influences igg effector function by modulating binding to fc receptors. to identify genetic loci associated with igg glycosylation,we quantitated n-linked igg glycans using two approaches. after isolating igg from human plasma,we performed 77 quantitative measurements of n-glycosylation using ultra-performance liquid chromatography (uplc) in 2,247 individuals from four european discovery populations. in parallel,we measured igg n-glycans using maldi-tof mass spectrometry (ms) in a replication cohort of 1,848 europeans. meta-analysis of genome-wide association study (gwas) results identified 9 genome-wide significant loci (p<2.27×10-9) in the discovery analysis and two of the same loci (b4galt1 and mgat3) in the replication cohort. four loci contained genes encoding glycosyltransferases (st6gal1,b4galt1,fut8,and mgat3),while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (ikzf1,il6st-ankrd55,abcf2-smarcd3,suv420h1,and smarcb1-derl3). however,most of them have been strongly associated with autoimmune and inflammatory conditions (e.g.,systemic lupus erythematosus,rheumatoid arthritis,ulcerative colitis,crohn's disease,diabetes type 1,multiple sclerosis,graves' disease,celiac disease,nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia,hodgkin lymphoma,and multiple myeloma). follow-up functional experiments in haplodeficient ikzf1 knock-out mice showed the same general pattern of changes in igg glycosylation as identified in the meta-analysis. as ikzf1 was associated with multiple igg n-glycan traits,we explored biomarker potential of affected n-glycans in 101 cases with sle and 183 matched controls and demonstrated substantial discriminative power in a roc-curve analysis (area under the curve = 0.842). our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using gwas. the results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer. © 2013 lauc et al.