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

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Genetic association and differential expression of HLA Complex Group lncRNAs in pemphigus
Journal of Autoimmunity ( IF 12.8 ) Pub Date : 2021-07-26 , DOI: 10.1016/j.jaut.2021.102705
Amanda Salviano-Silva ₁ , Mareike Becker ₂ , Danillo G Augusto ₃ , Hauke Busch ₂ , Gabriel Adelman Cipolla ₃ , Ticiana D-J Farias ₃ , Valéria Bumiller-Bini ₁ , Verónica Calonga-Solís ₃ , Matthias Munz ₂ , Andre Franke ₄ , Michael Wittig ₄ , Carolina M Camargo ₃ , Matthias Goebeler ₅ , Jennifer Elisabeth Hundt ₂ , Claudia Günther ₆ , Regine Gläser ₇ , Eva Hadaschik ₈ , Claudia Pföhler ₉ , Miklós Sárdy ₁₀ , Nina Van Beek ₁₁ , Margitta Worm ₁₂ , Detlef Zillikens ₁₁ , Angelica B W Boldt ₃ , Enno Schmidt ₁₃ , Maria Luiza Petzl-Erler ₃ , Saleh Ibrahim ₁₄ , Danielle Malheiros ₃

Affiliation

Postgraduate Program in Genetics. Department of Genetics, Federal University of Paraná (UFPR), Curitiba, Brazil; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
Postgraduate Program in Genetics. Department of Genetics, Federal University of Paraná (UFPR), Curitiba, Brazil.
Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany.
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Department of Dermatology, University Hospital, TU, Dresden, Germany.
Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany.
Department of Dermatology, Heidelberg, Germany.
Saarland University Medical Center, Department of Dermatology, Homburg, Germany.
Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany.
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Division of Allergy and Immunology, Department of Dermatology, Venerology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Lübeck, Lübeck, Germany.
Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.

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.

中文翻译：

HLA复合群lncRNA在天疱疮中的遗传关联和差异表达

背景

天疱疮是一组以棘层松解和皮肤水疱为特征的大疱性疾病。至于其他自身免疫性疾病，迄今为止发现的叶型天疱疮 (PF) 和寻常型天疱疮 (PV) 最强的遗传关联是与 HLA 基因的等位基因有关。然而，除了蛋白质编码基因外，MHC 区域还包括一组研究不足的长链非编码 RNA (lncRNA) 基因，即 HLA 复合群 (HCG)。

目标

调查 HCG lncRNA 等位基因是否与天疱疮易感性有关。

方法和结果

我们应用多元逻辑回归分析了 PV（德国：241 名患者；1,188 名对照）和地方性 PF（巴西：227 名患者；194 名对照）中 13 个 HCG lncRNA 基因的 SNP。我们发现 55 个与 PV ( p _corr < 0.01) 相关，9 个与地方性 PF ( p _corr < 0.05) 相关，大多数位于TSBP1-AS1（包括HCG23）和HCG27 lncRNA 基因，独立于先前与天疱疮相关的 HLA 等位基因。TSBP1-AS1 rs3129949*A等位基因的关联在散发性 PF 中进一步复制（p = 0.027，OR = 0.054；75 名患者和 150 名对照，均来自德国）。接下来，我们评估了巴西患者和对照的血液单核细胞中的TSBP1-AS1、TSBP1、HCG23和HCG27。HCG27在地方性 PF 中上调（p = 0.035，log ₂ FC = 1.3），而TSBP1-AS1在 PV 中下调（p = 0.029，log ₂ FC = -1.29）。在用来自德国的患者和对照的 IgG 抗体刺激的培养的角质形成细胞中也观察到相同的表达模式。地方性 PF 血细胞中的TSBP1 mRNA 水平也降低（p = 0.042，log ₂ FC = -2.14）。TSBP1-AS1和在地方性 PF的 CD19 ⁺细胞中也观察到HCG27下调（ p < 0.01，log ₂ FC = -0.226 和 -0.46）。