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<p>Pemphigus vulgaris (PV) is a rare autoimmune blistering disease mediated by pathogenic autoantibodies. 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–gene 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 &lt; 0.05). The FCGR2B c.671T &gt; C (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.</p>

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Genetic and immunological determinants of Pemphigus vulgaris: integrative analysis of HLA-DRB1 and FCGR2B variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Burak Kaan Kasap,
  • Bayram Toraman,
  • Burçin Kurt,
  • Hande Ermis,
  • Deniz Aksu Arıca

摘要

Pemphigus vulgaris (PV) is a rare autoimmune blistering disease mediated by pathogenic autoantibodies. 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–gene 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 < 0.05). The FCGR2B c.671T > C (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.