Thyroid autoimmunity in the TEDDY cohort: is HLA 8.1 haplotype the hidden driver?

To the Editor, We read with great interest the recent study by Clasen et al. regarding the temporal association between thyroid autoimmunity (anti-thyroid peroxidase antibodies [TPOAb]/anti-thyroglobulin antibodies [TGAb]) and the subsequent risk of islet autoimmunity (IA) and celiac disease autoimmunity (CDA) in the TEDDY cohort.1 The authors report a distinct “TPOAb-first” phenotype that significantly predicts the co-occurrence of IA and CDA. While these findings are clinically valuable, we propose that the interpretation of these trajectories would be significantly strengthened by stratifying the “high-risk” population—specifically the HLA-DR3 arm—according to their extended haplotype architecture. The TEDDY study recruits based on high-risk class II genotypes, specifically DRB1*03:01–DQB1*02:01.2 However, in populations of European descent, this class II pairing is genetically heterogeneous. It comprises 2 distinct groups: those carrying the conserved ancestral haplotype 8.1 (AH8.1) (defined as HLA-A*01–B*08–DRB1*03:01–DQB1*02:01–C4A*Q0) and those carrying “variant” DR3 haplotypes (eg, HLA-B*18–DRB1*03) which lack the unique class I and class III features of AH8.1.3