Genetic association and differential expression of HLAComplexGroup lncRNAs in pemphigus

Amanda Salviano-Silva; Mareike Becker; Danillo G Augusto; Hauke Busch; Gabriel Adelman Cipolla; Ticiana D-J Farias; Valéria Bumiller-Bini; Verónica Calonga-Solís; Matthias Munz; Andre Franke; Michael Wittig; Carolina M Camargo; Matthias Goebeler; Jennifer Elisabeth Hundt; Claudia Günther; Regine Gläser; Eva Hadaschik; Claudia Pföhler; Miklós Sárdy; Nina Van Beek; Margitta Worm; Detlef Zillikens; Angelica B W Boldt; Enno Schmidt; Maria Luiza Petzl-Erler; Saleh Ibrahim; Danielle Malheiros

doi:10.1016/j.jaut.2021.102705

Genetic association and differential expression of HLAComplexGroup lncRNAs in pemphigus

J Autoimmun. 2021 Sep:123:102705. doi: 10.1016/j.jaut.2021.102705. Epub 2021 Jul 26.

Authors

Amanda Salviano-Silva¹, Mareike Becker², Danillo G Augusto³, Hauke Busch², Gabriel Adelman Cipolla³, Ticiana D-J Farias³, Valéria Bumiller-Bini¹, Verónica Calonga-Solís³, Matthias Munz², Andre Franke⁴, Michael Wittig⁴, Carolina M Camargo³, Matthias Goebeler⁵, Jennifer Elisabeth Hundt², Claudia Günther⁶, Regine Gläser⁷, Eva Hadaschik⁸, Claudia Pföhler⁹, Miklós Sárdy¹⁰, Nina Van Beek¹¹, Margitta Worm¹², Detlef Zillikens¹¹, Angelica B W Boldt³, Enno Schmidt¹³, Maria Luiza Petzl-Erler³, Saleh Ibrahim¹⁴, Danielle Malheiros¹⁵

Affiliations

¹ Postgraduate Program in Genetics. Department of Genetics, Federal University of Paraná (UFPR), Curitiba, Brazil; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
² Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
³ Postgraduate Program in Genetics. Department of Genetics, Federal University of Paraná (UFPR), Curitiba, Brazil.
⁴ Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany.
⁵ Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
⁶ Department of Dermatology, University Hospital, TU, Dresden, Germany.
⁷ Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany.
⁸ Department of Dermatology, Heidelberg, Germany.
⁹ Saarland University Medical Center, Department of Dermatology, Homburg, Germany.
¹⁰ Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany.
¹¹ Department of Dermatology, University of Lübeck, Lübeck, Germany.
¹² Division of Allergy and Immunology, Department of Dermatology, Venerology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹³ Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Lübeck, Lübeck, Germany.
¹⁴ Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
¹⁵ Postgraduate Program in Genetics. Department of Genetics, Federal University of Paraná (UFPR), Curitiba, Brazil. Electronic address: dani_malheiros@ufpr.br.

PMID: 34325306
DOI: 10.1016/j.jaut.2021.102705

Abstract

Background: Pemphigus is a group of bullous diseases characterized by acantholysis and skin blisters. As for other autoimmune diseases, the strongest genetic associations found so far for pemphigus foliaceus (PF) and vulgaris (PV) are with alleles of HLA genes. However, apart from protein-coding genes, the MHC region includes a set of poorly explored long non-coding RNA (lncRNA) genes, the HLA complex group (HCG).

Objectives: To investigate if HCG lncRNA alleles are associated with pemphigus susceptibility.

Methods and results: We analyzed SNPs in 13 HCG lncRNA genes, both in PV (Germany: 241 patients; 1,188 controls) and endemic PF (Brazil: 227 patients; 194 controls), applying multivariate logistic regression. We found 55 associations with PV (p_corr < 0.01) and nine with endemic PF (p_corr < 0.05), the majority located in TSBP1-AS1 (which includes HCG23) and HCG27 lncRNA genes, independently of HLA alleles previously associated with pemphigus. The association of TSBP1-AS1 rs3129949*A allele was further replicated in sporadic PF (p = 0.027, OR = 0.054; 75 patients and 150 controls, all from Germany). Next, we evaluated the expression levels of TSBP1-AS1, TSBP1, HCG23, and HCG27 in blood mononuclear cells of Brazilian patients and controls. HCG27 was upregulated in endemic PF (p = 0.035, log₂ FC = 1.3), while TSBP1-AS1 was downregulated in PV (p = 0.029, log₂ FC = -1.29). The same expression patterns were also seen in cultured keratinocytes stimulated with IgG antibodies from patients and controls from Germany. TSBP1 mRNA levels were also decreased in endemic PF blood cells (p = 0.042, log₂ FC = -2.14). TSBP1-AS1 and HCG27 were also observed downregulated in CD19⁺ cells of endemic PF (p < 0.01, log₂ FC = -0.226 and -0.46 respectively).

Conclusions: HCG lncRNAs are associated with susceptibility to pemphigus, being TSBP1-AS1 and HCG27 also differentially expressed in distinct cell populations. These results suggest a role for HCG lncRNAs in pemphigus autoimmunity.

Keywords: Genetic susceptibility; HLA Complex group; Pemphigus; lncRNAs.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

HLA Antigens / genetics*
Humans
Keratinocytes / immunology
Pemphigus / genetics*
Pemphigus / immunology*
Polymorphism, Genetic
Polymorphism, Single Nucleotide
RNA, Long Noncoding / physiology*

Substances

HLA Antigens
RNA, Long Noncoding