## 4 Discussion  
The pathogenesis of pustular skin diseases is multifactorial and remains largely un-elucidated [26]. While genetic factors such as mutations in IL36 RN, CARD14, and AP153 are proposed to enhance the inflammatory cascade in several cellular subtypes, the high genetic heterogeneity of these diseases leads to ambiguous conclusions. The manifestation \begin{table}
\begin{tabular}{l c c c c c} \hline \hline
**Location** & **Alt** & **Accession ID** & **Binding Pocket** & **Odds** & **P** & **Emp P** \\ \hline
6:32580249 & C & rs9269744 & N & 0.048 & 0.020 & 0.004 \\ \hline
6:32581675 & G & rs77637983 & N & 0.035 & 0.009 & 0.001 \\ \hline
6:32584135 & C & rs17885482 & Y & 0.110 & 0.005 & \textless{}0.001 \\ \hline
6:32589702 & A & rs9270302 & N & 0.035 & 0.009 & 0.001 \\ \hline \hline \end{tabular} Abbreviation: Alt, alternative allele; AOID, adult-onset immunodeficiency; Odd, odd ratio; P, \(p\)-value; Enriched, significantly enriched in pustular skin disease dataset: Emp P: empirical \(p\)-value based on empirical distribution of 10,000 permutations.  
\end{table} 
Table 2: Association between HLA variants and pustular reaction in AOID using PP patients as control. of sterile pastules in PP, similar to AOID patients, provides a crucial clue for investigating common genetic factors that increase the risk of this phenotype. The association between HLA genes and immune-mediated diseases, including PP [27] and AOID [16], has been well documented. Therefore, we hypothesized that the HLA genes also play a role in pustule formation. In this study, specific HLA alleles were reported to be significantly associated with the presence of sterile skin pustules in pustular skin patients compared with the non-disease population, suggesting that HLA polymorphism is one of the genetic factors of the key etiopathogenesis in these pustular skin diseases. Specifically, in this study, we found that _HLA-B*13:01_, _HLA-C*03:04_, and _DQB1*05:02_ are shared in PP and pustular reaction in AOID, implying that, up to a certain point, there might be a common pathway contributing to pustule formation (Figure 2B). A thorough literature review concluded that there is no evidence of these HLA alleles in connection with any pustular diseases. Therefore, this is the first report suggesting the possible association of the aforementioned HLA alleles as a risk factor for pustular skin reaction. Interestingly, the _HLA-B*13:01_ allele has been shown to strongly correlate with hypersensitivity reactions to dapsone [28] and severe cutaneous adverse drug reactions to dapsone in the Thai population. As dapsone is considered as an alternative treatment for PP [29], caution should be used in prescribing dapsone in patients with PP. As was to be expected, there was also some divergence of _HLA-DPB1_ and _DRB1_ alleles between PP and pustular reaction in AOID, supporting the fact that they are separate entities evidenced by their distinctive extractutaneous features and other systemic manifestations. Notably, _HLA-DPB1*05:01_ showed significant association only with AOID patients with pustular skin reaction. Several studies have consistently shown that the _HLA-DPB1*05:01_ allele is associated with an increased risk of various autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosusous, aplastic anemia, and systemic sclerosis, particularly within the Asian population [30; 31; 32]. This underscores the significant role played by this allele in autoimmune conditions. Here, we report the first evidence of the _HLA-DPB1*05:01_ allele in association with the occurrence of pustular skin reaction in AOID patients, representing a novel biomarker to distinguish pustular skin reactions in AOID from PP patients. The _DRB1*15:01_[16] and _DRB1*15:02_[33] alleles have been previously reported to be related to AOID.