Variation in genes implicated in B‐cell development and antibody production affects susceptibility to pemphigus

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.

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

“…Among the markers of 20 additional candidate genes involved in B cell development and antibody production tested for associations in a previous work of our group ( Table S1 ), only the rs2070729*C allele of IRF1 (interferon regulatory factor 1) was associated with increased susceptibility to EPF [ 26 ]. The IRF1 has a broad range of functions in maintaining homeostasis and protecting the host from invading pathogens [ 143 ].…”

“…DNA from 227 EPF patients and 194 controls was extracted from peripheral blood by the phenol-chloroform-isoamyl alcohol protocol [ 25 ]. The individuals in this study were unrelated and predominantly of European ancestry [ 26 ]. The control individuals were not relatives of EPF patients and had no known autoimmune disease.…”

“…Patients were diagnosed by specialized dermatologists based on clinical characterization coupled with immunological tests, histopathology, and immunohistochemistry of skin biopsies. Patients and controls were recruited from the same geographical areas (Central–Western/Southeastern/Southern Brazilian hospitals) from 1984 to 2015, as previously reported by Calonga-Solís et al [ 26 ]. The mean age was 40.9 years for patients (minimum 6, maximum 83) and 44.8 years for controls (minimum 11, maximum 86).…”

“…Genotyping was performed by microarray hybridization (CoreExome-24 v1.1 Illumina) [ 31 ]. Among the 166 candidate genes, 20 were previously investigated in this same EPF cohort [ 26 , 32 , 33 ] and therefore were not genotyped in this study. We identified the genomic positions of each gene according to the GRCh37/hg19 human genome version, including segments of one thousand base pairs upstream and downstream from the transcription start and end sites, respectively, for the longest transcript.…”

Genetic Association and Differential RNA Expression of Histone (De)Acetylation-Related Genes in Pemphigus Foliaceus—A Possible Epigenetic Effect in the Autoimmune Response

“…They lived in Brazilian Midwest, Southeast, and South regions and were recruited in the Hospital Life 2024, 14, 60 3 of 17 Adventista do Pênfigo (Campo Grande, Mato Grosso do Sul), Lar da Caridade-Hospital do Fogo Selvagem (Uberaba, Minas Gerais), Hospital das Clínicas-Universidade de São Paulo (Ribeirão Preto, São Paulo), Hospital de Clínicas-Universidade Federal do Paraná, Hospital de Dermatologia Sanitária São Roque, and Hospital Santa Casa de Misericórdia (Curitiba, Paraná). Patients and controls were unrelated, of predominantly European ancestry [17], and had a similar sex ratio and age distribution: in both groups, 52% were women and the mean age of patients was 40.9 (6-83) years and of controls, 44.8 years. No patient had a history of other autoimmune diseases.…”