Identifying causal genetic variants for a given phenotype improves diagnosis and provides insights for designing therapies. However, defining the link and/or contribution to a phenotype of rare variants or those with an indirect contribution to disease remains challenging. These variants, however, are key for personalized and precision medicine strategies [1]. In this context, human leukocyte antigens of class II alleles (HLAIIs) facilitate activation of CD4+ T cells and are directly linked to various phenotypes. Non-classical HLAII (ncHLAII) molecules modulate HLAII function and their impact on T-cell responses. The contribution of ncHLAII to phenotypes has been investigated in knockout vs. wild-type cellular and animal models, and recent studies have shown that genetic variants altering the protein-coding regions of these molecules contribute to tuning of HLAII function [2]. These findings suggest that ncHLAII natural variants may play a key role in modulating immune mechanisms that affect human phenotypes.
