Immune genetic associations of antibody Fc-profiles across twins

Antibodies are bifunctional molecules that play a critical role in immune defense, both through their ability to recognize a near infinite number of targets via gene rearrangement and somatic hypermutation in their antigen-binding (Fab) region, and by directing the functional activity of the immune system via subclass/isotype switching and post-translational modifications of the fragment crystallizable (Fc) region. While genetic biases in Fab evolution have been demonstrated, less is known about the genetic regulation of Fc-biology. Thus, we comprehensively profiled 227 pathogen-specific antibody Fc-profiles to 20 antigens from 16 viral and bacterial pathogens and 2 allergens across a cohort of 510 monozygotic and dizygotic female twins. The majority of subclass, isotype, Fc-receptor binding, and Fc-effector functions show a degree of heritability. GWAS of the top 45 heritable phenotypes identified five genomic regions that are significantly associated with humoral traits and account for up to 33% of variance. Co-expression analysis in transcriptomic data indicated involvement of cytokine signaling, T cell help, and antigen presentation by myeloid cells as key potential regulators of Fc-biology. Collectively, these data highlight potential genetic mechanisms that govern Fc-biology. Fc-biology function may differ because of genetic heterogeneity. Here the authors profile antibody Fc-heterogeneity by comparing monozygotic and dizygotic twins and show evidence for heritability in specific genetic regions and implicate mediators such as cytokine signalling, T cell help and antigen presentation that may regulate Fc-biology.