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Pemphigus foliaceus (PF) is an autoimmune skin blistering disease characterized by antidesmoglein-1 IgG production, with an endemic form (EPF) in Brazil. Genetic and epigenetic factors have been associated with EPF, but its etiology is still not fully understood. To evaluate the genetic association of histone (de)acetylation-related genes with EPF susceptibility, we evaluated 785 polymorphisms from 144 genes, for 227 EPF patients and 194 controls. Carriers of <i>HDAC4_rs4852054*A</i> were more susceptible (OR = 1.79, <i>p</i> = 0.0038), whereas those with <i>GSE1_rs13339618*A</i> (OR = 0.57, <i>p</i> = 0.0011) and homozygotes for <i>PHF21A_rs4756055*A</i> (OR = 0.39, <i>p</i> = 0.0006) were less susceptible to EPF. These variants were not associated with sporadic PF (SPF) in German samples of 75 SPF patients and 150 controls, possibly reflecting differences in SPF and EPF pathophysiology. We further evaluated the expression of histone (de)acetylation-related genes in CD4⁺ T lymphocytes, using RNAseq. In these cells, we found a higher expression of <i>KAT2B</i>, <i>PHF20,</i> and <i>ZEB2</i> and lower expression of <i>KAT14</i> and <i>JAD1</i> in patients with active EPF without treatment compared to controls from endemic regions. The encoded proteins cause epigenetic modifications related to immune cell differentiation and cell death, possibly affecting the immune response in patients with PF.