## 4 Discussion
Additionally, the genetic insights garnered from our research could inform future clinical trials by identifying subsets of patients who are more likely to respond to specific treatments. This would not only enhance the efficacy and efficiency of such trials but also contribute to a more nuanced understanding of patient responsiveness to various therapeutic interventions. The knowledge gained from our study is instrumental in counseling patients and their families about the disease prognosis and management strategies, thereby contributing to a more comprehensive and holistic approach to patient care. A limitation of this study is the relatively small number of patients due to the rarity of the diseases. Also, a healthy control cohort collected in parallel with the case collection should be applied to avoid the confounding effect of geographic location. While the small patient sample is a limitation due to the rare nature of AOID, it is also a strength of this study that we were able to collect a substantial number of samples within this context. The 17 blood samples from AOID patients with pustular reactions, though limited, represent a significant achievement in studying such a rare condition. Coupled with the potential geographic bias and the absence of a control group, these limitations are balanced by the unique opportunity this study had in gathering data on a rare disease. The inclusion of acute generalized exanthematous pustulosis (AGEP) was constrained due to diagnostic practices, yet the HLA polymorphisms identified, particularly HLA-_DPBI*05:01_ and _DRBI*15:02_ alleles and the rs17885482 variant in _DRB1*15:01_, emerge as promising biomarkers for differentiating pustular skin diseases in AOID and PP patients. An additional limitation of this study is its potential lack of applicability to populations outside of Thailand. Given that our patient cohort predominantly comprises Thai individuals, the results may not be directly transferable to Western or African populations. This geographic and ethnic specificity should be considered when interpreting our findings, especially in the context of global applicability. Further studies involving diverse populations are necessary to validate and extend our results to a broader demographic spectrum. In expanding our investigation into the genetic underpinnings of pustular skin diseases, recent literature and whole-exome sequencing (WES) analyses have unveiled significant genetic variations beyond HLA polymorphisms. Notably, variations in six genes, IL1 RN, IL36 RN, CARD14, AP1S3, MPO, and TNIP1 [1], have been implicated in the pathophysiology of these conditions, enhancing the inflammatory response through the activation of IL-1 and IL-36 cytokine signaling pathways. This is particularly evident in dendritic cells, where IL-36 activation promotes the expression of HLA class II and co-stimulatory molecules CD80 and CD86 [38]. However, the high genetic heterogeneity of these diseases complicates the delineation of clear genetic risk variants, with known variants explaining only approximately one-third of the total case number [39]. This underscores the necessity for elucidating additional genetic predisposing factors. Recent WES analyses of three unrelated Thai patients revealed rare genetic variants within the SERPINB3 gene [40], linking GPP and AOID through common pathogenetic pathways and supporting the hypothesis of a shared genetic foundation. In conclusion, our study enriches the genetic discourse on pustular skin diseases by identifying HLA polymorphisms as potential biomarkers. However, the recognition of additional genetic variations emphasizes the complexity of these diseases' genetic architecture. Our findings lay the groundwork for future research, calling for a comprehensive approach to unravel the genetic predispositions of pustular skin diseases fully. This holistic exploration is crucial for developing targeted diagnostic and therapeutic strategies, thereby enhancing patient care and outcomes in the face of these challenging conditions.