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
N1 - Funding Information:
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.
Funding Information:
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/
Funding Information:
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/
Publisher Copyright:
© 2021 Elsevier Ltd
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.
KW - Genetic susceptibility
KW - HLA Complex group
KW - lncRNAs
KW - Pemphigus
UR - http://www.scopus.com/inward/record.url?scp=85111226664&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2021.102705
DO - 10.1016/j.jaut.2021.102705
M3 - Article
C2 - 34325306
AN - SCOPUS:85111226664
SN - 0896-8411
VL - 123
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
M1 - 102705
ER -
