Genetic Association and Differential RNA Expression of Histone (De)Acetylation-Related Genes in Pemphigus Foliaceus—A Possible Epigenetic Effect in the Autoimmune Response
Maiara Sulzbach Denardin,
Valéria Bumiller-Bini Hoch,
Amanda Salviano-Silva,
Sara Cristina Lobo-Alves,
Gabriel Adelman Cipolla,
Danielle Malheiros,
Danillo G. Augusto,
Michael Wittig,
Andre Franke,
Claudia Pföhler,
Margitta Worm,
Nina van Beek,
Matthias Goebeler,
Miklós Sárdy,
Saleh Ibrahim,
Hauke Busch,
Enno Schmidt,
Jennifer Elisabeth Hundt,
Maria Luiza Petzl-Erler,
Angelica Beate Winter Boldt
Affiliations
Maiara Sulzbach Denardin
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Valéria Bumiller-Bini Hoch
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Amanda Salviano-Silva
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Sara Cristina Lobo-Alves
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Gabriel Adelman Cipolla
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Danielle Malheiros
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Danillo G. Augusto
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Michael Wittig
Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, 24105 Kiel, Germany
Andre Franke
Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, 24105 Kiel, Germany
Claudia Pföhler
Department of Dermatology, Saarland University Medical Center, 66421 Homburg, Germany
Margitta Worm
Division of Allergy and Immunology, Department of Dermatology, Venerology and Allergy, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
Nina van Beek
Department of Dermatology, University of Lübeck, 23562 Lübeck, Germany
Matthias Goebeler
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany
Miklós Sárdy
Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany
Saleh Ibrahim
College of Medicine and Health Sciences, Khalifa University, Abu Dhabi 127788, United Arab Emirates
Hauke Busch
Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23562 Lübeck, Germany
Enno Schmidt
Department of Dermatology, University of Lübeck, 23562 Lübeck, Germany
Jennifer Elisabeth Hundt
Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23562 Lübeck, Germany
Maria Luiza Petzl-Erler
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
Angelica Beate Winter Boldt
Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná (UFPR), Curitiba 81531-980, Brazil
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 HDAC4_rs4852054*A were more susceptible (OR = 1.79, p = 0.0038), whereas those with GSE1_rs13339618*A (OR = 0.57, p = 0.0011) and homozygotes for PHF21A_rs4756055*A (OR = 0.39, p = 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 KAT2B, PHF20, and ZEB2 and lower expression of KAT14 and JAD1 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.
