Our present investigation of HLA-DRB1, centering on HLA-DR4 subtypes, reveals that three residues (β71, β74, β86) are responsible for variable associations of HLA-DR4 subtypes with time-to-seroconversion (reflecting etiology) and T1D (pathogenesis), supported by the two completely independent studies - a birth cohort and a population-based case-control study. This evidence concerns the gene HLA-DRB1 and type 1 diabetes mellitus.