S C Lobo-Alves1, D G Augusto1,2, W C S Magalhães3,4, E Tarazona-Santos4, M F Lima-Costa5, M L Barreto6, B L Horta7, R C de Almeida8, M L Petzl-Erler1. 1. Laboratório de Genética Molecular Humana, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil. 2. Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil. 3. Núcleo de Ensino e Pesquisa - NEP, Instituto Mário Penna, Belo Horizonte, Minas Gerais, Brazil. 4. Instituto de Ciências Biológicas, Departamento de Biologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. 5. Instituto de Pesquisa Rene Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil. 6. Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, BA, Brazil. 7. Programa de Pós-Graduação em Epidemiologia, Universidade Federal de Pelotas, Pelotas, RS, Brazil. 8. Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Abstract
BACKGROUND: Pemphigus foliaceus (PF) is an epidermal autoimmune disease, characterized by the presence of autoantibodies against the desmosomal protein desmoglein 1. Genetic and environmental factors contribute to PF, a complex disease that is endemic in Brazil and Colombia and neighbouring countries, and in Tunisia. Long noncoding RNAs (lncRNAs) may participate in gene regulation by interacting with DNA, proteins and other RNAs. Dysregulation of lncRNAs has recently been recognized as an important coplayer in the onset or progression of complex diseases. In addition, single-nucleotide polymorphisms (SNPs) located in lncRNA genes have been associated with differential risk to cancer, autoimmunity and infection. OBJECTIVES: Here, we aimed to investigate whether SNPs in lncRNA genes are associated with differential susceptibility to endemic PF. MATERIALS AND METHODS: We integrated data from the lncRNA SNP database with genome-wide genotype data obtained for 229 patients and 6681 controls. We tested the association between endemic PF and 2080 SNPs located in lncRNAs applying logistic regression. RESULTS: The most significantly associated SNP was rs7144332 (OR = 1·63, P = 2·8 × 10-6 ), located in the lncRNA gene AL110292·1. Results for five other SNPs were suggestive of association (P < 0·001). In silico analysis indicated that five of the six SNPs impact transcription, three may influence lncRNA's secondary structure, and three may alter microRNA-lncRNA interactions. CONCLUSIONS: We showed, for the first time, that variation in lncRNA genes may influence pemphigus pathogenesis. Our findings highlight the importance of lncRNA variation in autoimmune and possibly other complex diseases and suggest polymorphisms for functional validation.
BACKGROUND: Pemphigus foliaceus (PF) is an epidermal autoimmune disease, characterized by the presence of autoantibodies against the desmosomal protein desmoglein 1. Genetic and environmental factors contribute to PF, a complex disease that is endemic in Brazil and Colombia and neighbouring countries, and in Tunisia. Long noncoding RNAs (lncRNAs) may participate in gene regulation by interacting with DNA, proteins and other RNAs. Dysregulation of lncRNAs has recently been recognized as an important coplayer in the onset or progression of complex diseases. In addition, single-nucleotide polymorphisms (SNPs) located in lncRNA genes have been associated with differential risk to cancer, autoimmunity and infection. OBJECTIVES: Here, we aimed to investigate whether SNPs in lncRNA genes are associated with differential susceptibility to endemic PF. MATERIALS AND METHODS: We integrated data from the lncRNA SNP database with genome-wide genotype data obtained for 229 patients and 6681 controls. We tested the association between endemic PF and 2080 SNPs located in lncRNAs applying logistic regression. RESULTS: The most significantly associated SNP was rs7144332 (OR = 1·63, P = 2·8 × 10-6 ), located in the lncRNA gene AL110292·1. Results for five other SNPs were suggestive of association (P < 0·001). In silico analysis indicated that five of the six SNPs impact transcription, three may influence lncRNA's secondary structure, and three may alter microRNA-lncRNA interactions. CONCLUSIONS: We showed, for the first time, that variation in lncRNA genes may influence pemphigus pathogenesis. Our findings highlight the importance of lncRNA variation in autoimmune and possibly other complex diseases and suggest polymorphisms for functional validation.
Authors: Verónica Calonga-Solís; Leonardo M Amorim; Ticiana D J Farias; Maria Luiza Petzl-Erler; Danielle Malheiros; Danillo G Augusto Journal: Immunology Date: 2020-10-09 Impact factor: 7.397