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Summary: 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. What's already known about this topic? The multifactorial autoimmune blistering skin disease pemphigus foliaceus (PF) presents a genetic susceptibility component that is not fully understood.Although PF is rare worldwide, it reaches a prevalence of 1·5–3% in some regions of Brazil, the highest ever reported for an autoimmune disease.Long noncoding RNA (lncRNA) polymorphisms have been associated with some complex diseases but have not yet been studied in any form of pemphigus. What does this study add? Genetic variation of lncRNA may influence susceptibility to PF via its effect on lncRNA structure, on transcription of nearby genes, and on microRNA–lncRNA interactions.We have shown, for the first time, that variation in lncRNA genes may influence PF pathogenesis. What is the translational message? Our findings show that lncRNA variation is part of the polygenic risk component in the pathogenesis of pemphigus and possibly other complex skin diseases, indicating that lncRNAs can be explored as potential new drug targets. Linked Comment: Amber. Br J Dermatol 2019; 181:241–242. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

The study of the HLA variability of Native American populations revealed several alleles specific to one or more of the Latin American indigenous populations. The analysis of Amerindian groups distributed all over the continent might inform about the area of origin and the dispersal of these alleles and shed light on the evolution of this remarkable polymorphism. Moreover, HLA alleles and haplotypes are excellent markers to understand the genetic relationships between populations. For these reasons, we characterized the HLA class II polymorphism in seven South American Amerindian populations and compared the results with those previously reported for other Amerindian groups. The Guarani-Kaiowá ( n = 160) and Guarani-Ñandeva ( n = 87) were from the Brazilian state of Mato Grosso do Sul, the Guarani-M'byá ( n = 93) and Kaingang ( n = 235) from Paraná state, the Aché ( n = 89) from eastern Paraguay, the Quechua ( n = 44) from Andean Peru. From Amazonia, a heterogeneous group was analyzed ( n = 45). The most frequent alleles and haplotypes are common also in other Amerindian populations. Each HLA-DRB1 allele was typically found in combination with just one DQA1-DQB1 haplotype, most likely as a result of some form of random genetic drift and reduced gene flow from non-Amerindians. The frequency distribution differed significantly among all populations, although differences were less pronounced between the Guarani subgroups. Marker alleles allowed an estimate of European and sub-Saharan African gene flow into these populations: Quechua 23%, Guarani-Ñandeva 14%, Kaingang 7%, Guarani-M'byá 4%, Guarani-Kaiowá, Amazonia, and Aché 0%. Interestingly, the DRB1* 1413 allele, previously found only among the Guarani-M'byá (frequency 15%), appeared in the Aché (8%). The relationship of the Aché to other Amerindian populations is unclear, and this finding reveals a link with the Guarani. On the basis of genetic distance and the HLA allele/haplotype set, we propose that the Aché are differentiated Tupi-Guarani group, most closely related to the Guarani-M'byá. [ABSTRACT FROM AUTHOR]

The purpose of this study was to analyze the possible influence of the TNF and LTA loci polymorphisms on the susceptibility/resistance to endemic pemphigus foliaceus, also named fogo selvagem (FS), an autoimmune disease characterized by blisters due to acantholysis of the superficial-most epidermal cells. Autoantibodies, mainly of the IgG4 subclass, are directed against a desmosomal glycoprotein known as desmoglein 1. FS shares clinical, histological and immunological features with nonendemic pemphigus foliaceus. Most residents of the endemic regions do not develop the disease, and familial clustering has been documented, suggesting that host factors play a role in susceptibility. In fact, strong positive and negative associations with HLA class II genes have been reported. The TNF and LTA genes are located in the class III region of the Human Major Histocompatibility Complex. Their location, the function of their products, which are cytokines and pluripotent immunomodulators, as well as their genetic variability make them candidate genes for complex diseases with an altered immune response. A total of 162 patients and 191 controls were enrolled in this study. No significant associations were found with any one of the three LTA single nucleotide polymorphisms (SNP) analyzed (at nucleotides 249, 365, 720), nor with the TNF SNP located at positions −863 and −308. The frequency of allele TNF*238A was slightly decreased in patients (OR = 0.45). In conclusion, the results of this study indicate that genetic variability of the TNF and LTA genes does not play a major role in susceptibility/resistance to pemphigus foliaceus. [ABSTRACT FROM AUTHOR]

We identified a novel HLA-DRB1 allele, named DRB1*1340 by the WHO HLA Nomenclature Committee, in two Brazilian individuals. Typing by polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) showed a DRB1*13 allele with an unusual hybridization pattern. DNA sequencing of both strands and comparison of the sequence with previously described DRB1 alleles revealed that the most similar allele is DRB1*1301, from which DRB1*1340 differs by a single nucleotide (T→A) in exon 2, at position 127, codon 47 (Phe→Tyr). The sequence received accession number AJ237964 from the EMBL database. [ABSTRACT FROM AUTHOR]

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Summary: Pemphigus foliaceus (PF) is a disease that causes painful blisters in the skin. Due to genetic and environmental reasons, the person's own immune system produces antibodies that attack proteins present in the top layer of the skin (the epidermis). Although PF is rare worldwide, there are some geographic regions where many people develop this disease, known as the endemic form of PF (EPF). In Brazil, EPF is also known as fogo selvagem. This study aimed at finding out if single changes in the DNA (called SNPs – single nucleotide polymorphisms) located in genes called lncRNA genes predispose people to EPF. There are several different variants of SNPs. The frequencies of 2,080 SNPs were compared between 229 EPF patients and 6,681 people without pemphigus (the controls). A variant of the SNP called rs7144332 was significantly more frequent among EPF patients than people without EPF, and is therefore associated with increased risk. Results for another five SNPs suggested that they also influence the susceptibility to (risk of) EPF. Further study showed that five of these six SNPs could affect the amount of lncRNAs or proteins produced by nearby genes. Along with other findings, this study shows that genetic variants of lncRNAs might contribute to the development of pemphigus, highlighting their importance in autoimmune and possibly other complex diseases. Linked Article: Lobo‐Alves et al. Br J Dermatol 2019; 181:324–331 [ABSTRACT FROM AUTHOR]

Presents the polymorphism of TAP1, TAP2, LMP2 and LMP7 genes in the Kaingang and Guarani Amerindian tribes and the Caucasoid population of the Brazilian State of Panama. Concept of population genetics; Location of TAP and LMP genes in the major histocompatibility complex; Association between genetic variants and diseases.