Original Research ARTICLE
Polymorphisms in the mitochondrial genome are associated with bullous pemphigoid in Germans
- 1Lübeck Institute of Experimental Dermatology, University of Lübeck, Germany
- 2Institute for Cardiogenetics, Universität zu Lübeck, Germany
- 3Department of Dermatology, Allergology and Venereology, University Medical Center Schleswig-Holstein, Germany
- 4Forschungszentrum Borstel (LG), Germany
- 5Department of Dermatology, Venereology and Allergology, University Hospital Wuerzburg, Germany
- 6The German Autoimmune Bullous Disease Genetic Study Group, Germany
- 7Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Germany
- 8Other, Germany
- 9Department of Dermatology, University Hospital Carl Gustav Carus, Germany
- 10Department of Dermatology and Allergology, Philipps-University Marburg, Germany
- 11Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Germany
- 12Department of Dermatology and Venereology, Faculty of Medicine, Medical Center-University of Freiburg, Germany
- 13Department of Dermatology, Royal Melbourne Hospital, Australia
- 14Institute of Epidemiology, Faculty of Medicine, University of Kiel, Germany
- 15University of Kiel, Germany
- 16Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Hungary
- 17Department of Dermatology and Allergology, Ludwig Maximilian University of Munich, Germany
- 18Department of Dermatology, Venereology and Allergology, Charité Medical University of Berlin, Germany
Bullous pemphigoid (BP) is the most prevalent autoimmune skin blistering disease and is characterized by the generation of autoantibodies against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230. Most intriguingly, BP is distinct from other autoimmune diseases because it predominantly affects elderly individuals above the age of 75 years, raising the question why autoantibodies and the clinical lesions of BP emerges mostly in this later stage of life, even in individuals harboring known putative BP-associated germline gene variants.
The mitochondrial genome (mtDNA) is a potential candidate to provide additional insights into the BP etiology; however, the mtDNA has not been extensively explored to date. Therefore, we sequenced the whole mtDNA of German BP patients (n=180) and age- and sex-matched healthy controls (n=188) using next generation sequencing (NGS) technology, followed by the replication study using Sanger sequencing of an additional independent BP (n=89) and control cohort (n=104). While the BP and control groups showed comparable mitochondrial haplogroup distributions, the haplogroup T exhibited a tendency of higher frequency in BP patients suffering from neurodegenerative diseases (ND) compared to BP patients without ND (p= 0.1448, Fisher’s exact test). A total of four single nucleotide polymorphisms (SNPs) in the mtDNA, namely, m.16263T>C, m.11914G>A, m.16051A>G, and m.16162A>G, were found to be significantly associated with BP based on the meta-analysis of our NGS data and the Sanger sequencing data (p=0.0017, p=0.0132, p=0.0129, and p=0.0076, respectively, Peto’s test).
In summary, our study is the first to interrogate the whole mtDNA in BP patients and controls and to implicate multiple novel mtDNA variants in disease susceptibility. Studies using larger cohorts and more diverse populations are warranted to explore the functional consequences of the mtDNA variants identified in this study on immune and skin cells to understand their contributions to BP pathology.
Keywords: mitochondrial DNA, Mitochondrial haplogroup, polymorphisms, Autoimmune skin disease, Bullous pemphigoid, Mitochondrial function, next generation sequencing
Received: 31 May 2019;
Accepted: 30 Aug 2019.
Copyright: © 2019 Russlies, Fähnrich, Witte, Yin, Benoit, Gläser, Günther, Eming, Erdmann, Gola, Gupta, Holtsche, Kern, König, Kiritsi, Lieb, Sadik, Sárdy, Schauer, van Beek, Weidinger, Worm, Zillikens, Schmidt, Busch, Ibrahim and Hirose. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Misa Hirose, Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany, Misa.Hirose@uksh.de