Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns

Annika Wahl, Erik van den Akker, Lucija Klaric, Jerko Štambuk, Elisa Benedetti, Rosina Plomp, Genadij Razdorov, Irena Trbojević-Akmačić, Joris Deelen, Diana van Heemst, P. Eline Slagboom, Frano Vučković, Harald Grallert, Jan Krumsiek, Konstantin Strauch, Annette Peters, Thomas Meitinger, Caroline Hayward, Manfred Wuhrer, Marian Beekman, Gordan Lauc, Christian Gieger

Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with a wide range of diseases. Glycosylation of the Fc binding region of IgGs, responsible for the antibody's effector function, is essential for prompting a proper immune response. This study focuses on the general genetic impact on IgG glycosylation as well as corresponding subclass specificities. To identify genetic loci involved in IgG glycosylation, we performed a genome-wide association study (GWAS) on liquid chromatography electrospray mass spectrometry (LC-ESI-MS)-measured IgG glycopeptides of 1,823 individuals in the Cooperative Health Research in the Augsburg Region (KORA F4) study cohort. In addition, we performed GWAS on subclass-specific ratios of IgG glycans to gain power in identifying genetic factors underlying single enzymatic steps in the glycosylation pathways. We replicated our findings in 1,836 individuals from the Leiden Longevity Study (LLS). We were able to show subclass-specific genetic influences on single IgG glycan structures. The replicated results indicate that, in addition to genes encoding for glycosyltransferases (i.e.,ST6GAL1, B4GALT1, FUT8, andMGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboringRUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of theRUNXfamily are cross-regulated, andRUNX3is involved in both IgA class switching and B-cell maturation as well as T-cell differentiation and apoptosis. Besides the involvement of glycosyltransferases in IgG glycosylation, we suggest that, due to the impact of variants withinRUNX3, potentially mechanisms involved in B-cell activation and T-cell differentiation during the immune response as well as cell migration and invasion involve IgG glycosylation.