Variation in genes implicated in B‐cell development and antibody production affects susceptibility to pemphigus. Issue 1 (9th October 2020)

• Record Type: Journal Article
• Authors: Calonga‐Solís, Verónica; Amorim, Leonardo M.; Farias, Ticiana D. J.; Petzl‐Erler, Maria Luiza; Malheiros, Danielle; Augusto, Danillo G.
• Is Part Of: Immunology. Volume 162:Issue 1(2021)
• Page Start: 58
• Page End: 67
• Publication Date: 2020-10-09
• Subjects: genetics -- immunogenetics -- immunoglobulin -- immunology -- pemphigus foliaceus; Immunology -- Periodicals
• DOI: 10.1111/imm.13259
• Languages: English
• ISSNs: 0019-2805

Abstract

Abstract: Pemphigus foliaceus (PF) is an autoimmune blistering skin disease characterized by the presence of pathogenic autoantibodies against desmoglein 1, a component of intercellular desmosome junctions. PF occurs sporadically across the globe and is endemic in some Brazilian regions. Because PF is a B‐cell‐mediated disease, we aimed to study the impact of variants within genes encoding molecules involved in the different steps of B‐cell development and antibody production on the susceptibility of endemic PF. We analysed 3, 336 single nucleotide polymorphisms (SNPs) from 167 candidate genes genotyped with Illumina microarray in a cohort of 227 PF patients and 193 controls. After quality control and exclusion of non‐informative and redundant SNPs, 607 variants in 149 genes remained in the logistic regression analysis, in which sex and ancestry were included as covariates. Our results revealed 10 SNPs within or nearby 11 genes that were associated with susceptibility to endemic PF (OR >1.56; p < 0.005): rs6657275*G ( TGFB2 ); rs1818545*A ( RAG1 / RAG2 / IFTAP) ; rs10781530*A ( PAXX ), rs10870140*G and rs10781522*A ( TRAF2 ); rs535068*A ( TNFRSF1B ); rs324011*A ( STAT6) ; rs6432018*C ( YWHAQ) ; rs17149161*C ( YWHAG) ; and rs2070729*C ( IRF1) . Interestingly, these SNPs have been previously associated with differential gene expression, mostly in peripheral blood, in publicly available databases. For the first time, we show that polymorphisms in genes involved in B‐cell development and antibody production confer differential susceptibility to endemic PF, and therefore are candidates for possible functional studies to understand immunoglobulin gene rearrangement and its impact on diseases. Abstract : Pemphigus foliaceus (PF) is a B‐cell‐mediated autoimmune skin disease found sporadically across the globe but endemic and highly prevalent in Brazil. The analysis of 167 genes knowingly implicated in antibody production and B‐cell development revealed 10 single nucleotide polymorphisms within or nearby 11 genes that were associated with susceptibility to endemic PF. Our unprecedented study includes a comprehensive in silico analysis suggesting that regulation of molecules involved in B‐cell activation, immunoglobulin isotype switching and hypermutation may explain the genetic associations.