## 4 Discussion
Interestingly, in our study, the _DRB1*15:01_ allele was related to pustular reaction in PP patients, whereas the _DRB1*15:02_ allele was related to pustular reaction in AOID patients using healthy individuals as the control group. Our subsequent investigation comparing patients with pustular reaction in AOID to those with pustular reaction in PP revealed significant results confirming this signal in the _DRB1*15:02_ allele. The amino acid sequence alignment of the _DRB1*15:01_ and the _DRB1*15:02_ alleles revealed that both sequences are nearly identical, with only one amino acid difference at position 115 (p.Val115 Gly) (Supplementary Figure S1). Therefore, further investigation on this variant is required to determine its impact on the antigen presentation process and pathogenesis of the two diseases. Interestingly, a number of HLA class II missense variants, i.e., _HLA-DPB1_, _DRB1_, and _DQB1_, that are enriched in this dataset are more in the antigen-binding groove (67%, 64%, and 60%, respectively) compared to class I, i.e., _HLA-B_ (48%) and _HLA-C_ (53%). This high variation in the binding groove of HLA class II may play an important role in the disease pathogenesis by altering regulation or lowering the selection threshold for autoreactive T cells during T-cell development in the thymus [34; 35]. Among these variants, we again identified rs17885482 (p.Val115 Gly) in the _HLA-DRB1_ gene as a biomarker for separating pustular skin reactions in AOID and PP patients. Numerous studies have shown that the variants on the HLA-DR binding groove could directly impact the binding affinity of exogenous antigens in presenting to CD4+ T cells and relate to autoimmune disease [34; 36; 37]. Therefore, particular environmental triggers might be involved in predisposing individuals to pustular skin diseases. The therapeutic implications of our study on both AOID and PP are extensive and multifaceted, especially in the context of early diagnosis and tailored interventions. Ourinsights into specific HLA polymorphisms serve as an important element in enhancing diagnostic accuracy enabling early identification of individuals presenting with multiple sterile skin pustules without known documented underlying conditions. This early detection, facilitated by the identified specific HLA polymorphisms, offers a potential for timely and effective therapeutic interventions, which is critical given the nature of AOID and PP where a delay in diagnosis can lead to advanced disease progression and increased morbidity. Our research may contribute to understanding factors that could potentially reduce the mortality rate associated with these diseases by allowing for the early identification of at-risk individuals and the development of targeted treatment protocols. Interestingly, nearly all AOID patients reported to date originate from Asia or have Asian ancestry, even if they reside elsewhere [4]. This suggests a notable racial predisposition within the population. Our study contributes significantly to the understanding of AOID's prevalence and characteristics, especially in East and Southeast Asian populations. It highlights the influence of specific infections or environmental factors unique to these regions and underscores the pronounced linkage of the disease to the Japanese population. This geographical and ethnic specificity is vital for clinicians to consider in the clinical interpretation of AOID and similar conditions, as it provides essential insights into the disease's etiology and the tailoring of treatment strategies. However, it is important to note the limitation in our findings' applicability to Western or African populations, given the almost exclusive Thai background of our patient cohort. This highlights the need for further research involving diverse demographic settings to validate and expand upon our findings, ensuring global applicability and relevance.