## 3 Results
### HLA Types Are Associated with Pustular Skin Diseases  
HLA typing of 41 patients with pustular skin diseases was carried out based on next-generation sequencing (NGS) technology. The frequencies of HLA class I (A, B, and C) and class II (DPB1, DQB1, and DRB1) alleles identified in this study are summarized in Supplementary Table S1. In our cohort, _HLA-A*11:01_ (AF = 0.280), _HLA-B*13:01_ (AF = 0.195), and _HLA-C*03:04_ (AF = 0.244) were mostly observed for HLA class I, and _HLA-DQB1*05:02_ (AF = 0.366), _DRB1*15:02_ (AF = 0.232), and _DPB1*05:01_ (AF = 0.305) were mostly observed for HLA class II. Interestingly, patients who carry at least one of the _DQB1*05:01_ or _DQB1*05:02_ alleles account for 76% of the dataset. Moreover, 73% of the patients in this cohort carry at least one _DRB1*15:01_ or _DRB1*15:02_ allele and one _DPB1*05:01_ or _DPB1*13:01_ allele. The association between the patients who carry pustular skin diseases and HLA alleles was evaluated by comparing them with the HLA allele frequency of the Thai healthy population (N = 470) randomly chosen from five regional groups of Thailand reported in [PERSON] et al., 2020 [21]. We observed that seven HLA alleles, three from HLA class I and four alleles from class II, were significantly associated with pustular skin diseases, i.e., _HLA-B*13:01_ (OR = 3.825, 95%CI: 2.08-7.035), _B*18:02_ (OR = 3.154, 95%CI: 1.002-9.73), _C*03:04_ (OR = 3.665, 95%CI: 2.102-6.39), _DQB1*03:01_ (OR = 0.448, 95%CI: 2.023-0.991), _DQB1*05:02_ (OR = 2.134, 95%CI: 1.326-3.434), _DRB1*15:01_ (OR = 2.971, 95%CI: 1.658-5.324), and _DRB1*15:02_ (OR = 1.783, 95%CI: 1.034-3.072) (Table 1). To confirm these associations, we applied different control groups and observed the consensus. The HLA allele frequency of the Thai healthy population (N = 334) from a dengue vaccine efficacy trial conducted in Ratchaburi Province in Thailand and reported by [PERSON] et al., 2018 [20], was used as a control group for validation. We found that six of the seven HLA alleles remained significantly associated with pustular skin diseases, i.e., _HLA-B*13:01_ (OR = 3.909, 95%CI: 2.072-7.274), _C*03:04_ (OR = 3.745, 95%CI: 2.103-6.668), _DQB1*03:01_ (OR = 0.398, 95%CI: 0.179-0.884), _DQB1*05:02_ (OR = 2.557, 95%CI: 1.566-4.174), _DRB1*15:01_ (OR = 2.805, 95%CI: 1.541- 5.105), and _DRB1*15:02_ (OR = 2.576, 95%CI: 1.457-4.554) (Supplementary Table S2). There were additional significantly associated alleles when the latter was used as a control group, i.e., _HLA-A*33:03_ (OR = 0.338, 95%CI: 0.121-0.947), _A*13:01_ (OR = 0.391, 95%CI: 2.072-7.374), _DPB1*05:01_ (OR = 3.746, 95%CI: 2.202-6.374), _DQB1*05:01_ (OR = 2.233, 95%CI: 1.158-4.307), and _DRB1*16:02_ (OR = 2.23, 95%CI: 1.031-4.823). However, it is important to note that the _HLA-DPB1_ gene was not present in the first comparison because it was not included by the original study. Therefore, we included the _DPB1_ gene in the overlapped list, which was _B*13:01_, _C*03:04_, _DPB1*05:01_, _DQB1*03:01_, _DQB1*05:02_, _DRB1*15:01_, and _DRB1*15:02_. These seven alleles were associated with the patients who developed sterile skin pustules consistently from both control datasets. Of these, six alleles were observed to increase the risk of pustular skin reaction (OR > 1), and only _DQB1*03:01_ was observed to have a protective role against the reaction (OR < 1). We further evaluated the association of these alleles in each disease group of the pulsutular diseases. Of those seven alleles, the association of three' alleles remained significant in both separated conditions of AOID vs. healthy and PP vs. healthy, i.e., _B*13:01_, _C*03:04_, and _DQB1*05:02_ (Supplementary Tables S3 and S4), while the association of _DQB1*03:01_ disappeared from both conditions (Figure 2B).