Genome-wide association analysis of diverse immune-related phenotypes highlights complex overlapping pathways of immune response. J. Y. Tung, N. Eriksson, A. K. Kiefer, D. A. Hinds 23andMe, Inc, Mountain View, CA.
The immune systems defense of the body against assault requires a complex interplay of cell-mediated and humoral immunity including a multitude of cell types, antigen processing and presentation systems, cytokines, and inflammatory factors. As a result, teasing out which components underlie each individuals susceptibility to immunological conditions is a daunting task. Genome-wide analyses studying these conditions can shed light on which pathways play the biggest roles for different types of conditions. We compared the top associations for a diverse set of inflammatory phenotypes including poison oak contact dermatitis, mosquito bite size, and tonsillectomy (as a proxy for chronic tonsillitis) with each other and with published associations with autoimmune, allergic, and infectious conditions. For inflammatory phenotypes, significant hits near IL21 and GMCSF2(mosquito bite size) and OSM, LTBR, CXCL13, IGFBP3, and IKZF1 (tonsillectomy) suggest a more prominent role for cytokines and inflammatory pathways for these conditions than in allergy or infectious disease. There are several overlaps as well. For tonsillectomy, the variant near IKZF1 is in high linkage disequilibrium with a variant strongly associated with systemic lupus erythematosus, an autoimmune condition. The region near IL2 and IL21 associated with mosquito bite size is also associated with allergy, though the respective variants are not closely linked. In addition, like for many autoimmune, allergic, and infectious conditions, the HLA region comes up as an important hit for both mosquito bite size and tonsillectomy. In our data, the same variant between HLA-B and MICA (rs138099588) associated with tonsillectomy is also strongly associated with psoriasis (p = 6.57e-52) and shingles (p = 2.05e-8). For poison oak contact dermatitis, we see a hit within a cluster of CD1 genes on chromosome 1, rather than in the HLA region. CD1 proteins mediate presentation of lipids to T cells (instead of proteins like the major histocompatibility complex molecules). This is consistent with the role of urushiol, the oily substance produced by the poison oak plant, in triggering the dermatitis. These results highlight the myriad of mechanisms used by the immune system, as well as the subtle similarities and differences in those mechanisms, to react to toxic substances and invaders in the environment.