The discovery of pathogenic variants provided biological insight into the role of host genetic factors in generalized pustular psoriasis (GPP). However, not all those affected by GPP carry variants in the reported genes. To comprehensively explore the molecular pathogenesis of GPP, whole-exome sequencing was performed, and two loci were identified with exome-wide significance through single variant association analysis: rs148755083 in the IL36RN gene (Pcombined = 1.19 × 10-18, OR = 8.26) and HLA-C∗06:02 within the major histocompatibility complex region (Pcombined = 8.38 × 10-12, OR = 2.98). Gene burden testing revealed that BTN3A3 correlated with GPP (Pcombined = 1.14 × 10-10, OR = 5.59). Subtype analysis showed that IL36RN and BTN3A3 were both significantly associated with GPP alone and GPP with psoriasis vulgaris, whereas a correlation with HLA-C∗06:02 was only observed in GPP with psoriasis vulgaris. Functional analysis revealed that BTN3A3 regulated cell proliferation and inflammatory balance in GPP. In particular, loss of function of BTN3A3 activated NF-κB and promoted the production of inflammatory cytokines by inhibiting IL-36Ra expression to disturb the IL-1/IL-36 inflammatory axis and enhance the TNF-α-mediated pathway. Our findings identify BTN3A3 as, to our knowledge, a previously unreported pathogenic determinant, expanding our understanding of the genetic basis of GPP.
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