Genetic association and differential expression of HLA Complex Group 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 HLA Complex Group 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 BeekMargitta Worm, Detlef Zillikens, Angelica B.W. Boldt, Enno Schmidt, Maria Luiza Petzl-Erler, Saleh Ibrahim, Danielle Malheiros^*

^*Corresponding author for this work

12 Citations (Scopus)

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.

Original language	English
Article number	102705
Journal	Journal of Autoimmunity
Volume	123
ISSN	0896-8411
DOIs	https://doi.org/10.1016/j.jaut.2021.102705
Publication status	Published - 09.2021

Funding

This work was supported by grants of the following funding agencies: Funda??o Arauc?ria (FA protocol 39894.413.43926.1904/2013), FA/PRONEX (116/2018, protocol 50530), Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq protocol 470483/2014?8), and Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior Superior (CAPES), with post-doc scholarship with bench rate for DA (CNPq protocol 400648/2014?8), and CAPES/PROAP Finance Code 001, Co-financed Short-Term Research Grant Brazil (2018 for TDJF; 2019 for AS-S, VB-B) by Deutscher Akademischer Austauschdienst (DAAD), and the German Research Foundation under Germany's Excellence Strategy (EXC 2167?390884018; HB, DZ, ES). TDJF received a scholarship under the International Sandwich Doctorate Program (PDSE) from CAPES (PDSE process 88881.132221/2016?01). GAC received a postdoctoral scholarship from CAPES (protocol number 88882.306040/2018?01). ABWB receives a research productivity scholarship from CNPq (protocol number 314288/2018?0). The funding agencies had no role in study design, sample collection, data analysis and interpretation, and manuscript drafting and submission.We gratefully acknowledge the patients and all other volunteer subjects for their participation in this study. We also thank the staff of the Laborat?rio de Gen?tica Molecular Humana/UFPR for their assistance and helpful discussions, as well as the investigators of the German Autoimmune Bullous Diseases Study Group and funding sources. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: https://gtexportal.org/home/snp/ This work was supported by grants of the following funding agencies: Fundação Araucária (FA protocol 39894.413.43926.1904/2013 ), FA/PRONEX ( 116/2018 , protocol 50530), Conselho Nacional de Desenvolvimento Científico e Tecnológico ( CNPq protocol 470483/2014–8 ), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Superior ( CAPES ), with post-doc scholarship with bench rate for DA ( CNPq protocol 400648/2014–8 ), and CAPES /PROAP Finance Code 001, Co-financed Short-Term Research Grant Brazil (2018 for TDJF; 2019 for AS-S, VB-B) by Deutscher Akademischer Austauschdienst (DAAD), and the German Research Foundation under Germany's Excellence Strategy (EXC 2167–390884018; HB , DZ, ES ). TDJF received a scholarship under the International Sandwich Doctorate Program (PDSE) from CAPES (PDSE process 88881.132221/2016–01 ). GAC received a postdoctoral scholarship from CAPES (protocol number 88882.306040/2018–01). ABWB receives a research productivity scholarship from CNPq (protocol number 314288/2018–0). The funding agencies had no role in study design, sample collection, data analysis and interpretation, and manuscript drafting and submission. We gratefully acknowledge the patients and all other volunteer subjects for their participation in this study. We also thank the staff of the Laboratório de Genética Molecular Humana / UFPR for their assistance and helpful discussions, as well as the investigators of the German Autoimmune Bullous Diseases Study Group and funding sources. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health , and by NCI , NHGRI , NHLBI , NIDA , NIMH , and NINDS . The data used for the analyses described in this manuscript were obtained from: https://gtexportal.org/home/snp/

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.22-19 Dermatology
2.21-05 Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaut.2021.102705

Cite this

Salviano-Silva, A., Becker, M., Augusto, D. G., Busch, H., Adelman Cipolla, G., Farias, T. D. J., Bumiller-Bini, V., Calonga-Solís, V., Munz, M., Franke, A., Wittig, M., Camargo, C. M., Goebeler, M., Hundt, J. E., Günther, C., Gläser, R., Hadaschik, E., Pföhler, C., Sárdy, M., ... Malheiros, D. (2021). Genetic association and differential expression of HLA Complex Group lncRNAs in pemphigus. Journal of Autoimmunity, 123, Article 102705. https://doi.org/10.1016/j.jaut.2021.102705

@article{64c643c6ee204997955d8a9da23431b6,

title = "Genetic association and differential expression of HLA Complex Group lncRNAs in pemphigus",

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 (pcorr < 0.01) and nine with endemic PF (pcorr < 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.",

author = "Amanda Salviano-Silva and Mareike Becker and Augusto, \{Danillo G.\} and Hauke Busch and \{Adelman Cipolla\}, Gabriel and Farias, \{Ticiana D.J.\} and Val{\'e}ria Bumiller-Bini and Ver{\'o}nica Calonga-Sol{\'i}s and Matthias Munz and Andre Franke and Michael Wittig and Camargo, \{Carolina M.\} and Matthias Goebeler and Hundt, \{Jennifer Elisabeth\} and Claudia G{\"u}nther and Regine Gl{\"a}ser and Eva Hadaschik and Claudia Pf{\"o}hler and Mikl{\'o}s S{\'a}rdy and \{Van Beek\}, Nina and Margitta Worm and Detlef Zillikens and Boldt, \{Angelica B.W.\} and Enno Schmidt and Petzl-Erler, \{Maria Luiza\} and Saleh Ibrahim and Danielle Malheiros",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = sep,

doi = "10.1016/j.jaut.2021.102705",

language = "English",

volume = "123",

journal = "Journal of Autoimmunity",

issn = "0896-8411",

publisher = "Academic Press",

}

Salviano-Silva, A, Becker, M, Augusto, DG, Busch, H, Adelman Cipolla, G, Farias, TDJ, Bumiller-Bini, V, Calonga-Solís, V, Munz, M, Franke, A, Wittig, M, Camargo, CM, Goebeler, M, Hundt, JE, Günther, C, Gläser, R, Hadaschik, E, Pföhler, C, Sárdy, M, Van Beek, N, Worm, M, Zillikens, D, Boldt, ABW, Schmidt, E, Petzl-Erler, ML, Ibrahim, S & Malheiros, D 2021, 'Genetic association and differential expression of HLA Complex Group lncRNAs in pemphigus', Journal of Autoimmunity, vol. 123, 102705. https://doi.org/10.1016/j.jaut.2021.102705

TY - JOUR

T1 - Genetic association and differential expression of HLA Complex Group lncRNAs in pemphigus

AU - Salviano-Silva, Amanda

AU - Becker, Mareike

AU - Augusto, Danillo G.

AU - Busch, Hauke

AU - Adelman Cipolla, Gabriel

AU - Farias, Ticiana D.J.

AU - Bumiller-Bini, Valéria

AU - Calonga-Solís, Verónica

AU - Munz, Matthias

AU - Franke, Andre

AU - Wittig, Michael

AU - Camargo, Carolina M.

AU - Goebeler, Matthias

AU - Hundt, Jennifer Elisabeth

AU - Günther, Claudia

AU - Gläser, Regine

AU - Hadaschik, Eva

AU - Pföhler, Claudia

AU - Sárdy, Miklós

AU - Van Beek, Nina

AU - Worm, Margitta

AU - Zillikens, Detlef

AU - Boldt, Angelica B.W.

AU - Schmidt, Enno

AU - Petzl-Erler, Maria Luiza

AU - Ibrahim, Saleh

AU - Malheiros, Danielle

PY - 2021/9

Y1 - 2021/9

N2 - 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 (pcorr < 0.01) and nine with endemic PF (pcorr < 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.

AB - 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 (pcorr < 0.01) and nine with endemic PF (pcorr < 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.

UR - https://www.scopus.com/pages/publications/85111226664

UR - https://www.mendeley.com/catalogue/17427139-86c2-35fd-8cdd-c8e77b7ab381/

U2 - 10.1016/j.jaut.2021.102705

DO - 10.1016/j.jaut.2021.102705

M3 - Journal articles

AN - SCOPUS:85111226664

SN - 0896-8411

VL - 123

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

M1 - 102705

ER -

Genetic association and differential expression of HLA Complex Group lncRNAs in pemphigus

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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