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Although both HLA and non-HLA loci contribute to disease susceptibility, their combined roles in immune regulation remain incompletely understood. This study investigated the joint contribution of HLA-DRB1 and FCGR2B variants to PV susceptibility within an integrative immunogenetic framework. Genotype data from 286 individuals (200 controls and 86 PV patients) were analyzed using bias-reduced association models, two-locus genotype combination analyses, and cumulative genetic risk modeling. Gene\u2013gene relationships were explored through epistasis testing, while functional relevance was examined using biological annotation approaches. HLA-DRB1*04:02 and *14:01 were significantly associated with increased PV risk, whereas *11:01 and *16:01 demonstrated protective effects after multiple testing correction (q\u2009&lt;\u20090.05). The FCGR2B c.671T\u2009&gt;\u2009C (I232T) variant showed a modest effect in single-locus analyses but did not remain statistically significant after correction for multiple testing. Several two-locus genotype combinations involving FCGR2B and HLA-DRB1 were enriched among patients; however, interaction analyses supported an additive immunogenetic architecture rather than epistasis. Genetic risk modeling demonstrated improved discrimination with weighted scores, and explainable machine-learning analysis identified HLA-DRB1 as the dominant predictor, with FCGR2B contributing a secondary modulatory signal. These findings delineate an additive immunogenetic framework underlying PV susceptibility, emphasizing the central role of HLA-DRB1. Although FCGR2B did not retain independent statistical significance after multiple-testing correction, the results suggest a potential modulatory contribution within the broader immunogenetic architecture of PV.<\/jats:p>","DOI":"10.1007\/s00251-026-01402-5","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:39:21Z","timestamp":1779237561000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic and immunological determinants of Pemphigus vulgaris: integrative analysis of HLA-DRB1 and FCGR2B variants"],"prefix":"10.1007","volume":"78","author":[{"given":"Burak Kaan","family":"Kasap","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bayram","family":"Toraman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5781-2382","authenticated-orcid":false,"given":"Bur\u00e7in","family":"Kurt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hande","family":"Ermis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deniz Aksu","family":"Ar\u0131ca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"1402_CR14","volume-title":"Categorical data analysis","author":"A Agresti","year":"2013","unstructured":"Agresti A (2013) Categorical data analysis, 3rd edn. 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