Beyond the HLA polymorphism: A complex pattern of genetic susceptibility to pemphigus

Abstract

Pemphigus is a group of autoimmune bullous skin diseases that result in significant morbidity. As for other multifactorial autoimmune disorders, environmental factors may trigger the disease in genetically susceptible individuals. The goals of this review are to summarize the state of knowledge about the genetic variation that may affect the susceptibility and pathogenesis of pemphigus vulgaris and pemphigus foliaceus-both the endemic and the sporadic forms-, to compare and discuss the possible meaning of the associations reported, and to propose recommendations for new research initiatives. Understanding how genetic variants translate into pathogenic mechanisms and phenotypes remains a mystery for most of the polymorphisms that contribute to disease susceptibility. However, genetic studies provide a strong foundation for further developments in this field by generating testable hypotheses. Currently, results still have limited influence on disease prevention and prognosis, drug development, and clinical practice, although the perspectives for future applications for the benefit of patients are encouraging. Recommendations for the continued advancement of our understanding as to the impact of genetic variation on pemphigus include these partially overlapping goals: (1) Querying the functional effect of genetic variants on the regulation of gene expression through their impact on the nucleotide sequence of cis regulatory DNA elements such as promoters and enhancers, the splicing of RNA, the structure of regulatory RNAs and proteins, binding of these regulatory molecules to regulatory DNA elements, and alteration of epigenetic marks; (2) identifying key cell types and cell states that are implicated in pemphigus pathogenesis and explore their functional genomes; (3) integrating structural and functional genomics data; (4) performing disease-progression longitudinal studies to disclose the causal relationships between genetic and epigenetic variation and intermediate disease phenotypes; (5) understanding the influence of genetic and epigenetic variation in the response to treatment and the severity of the disease; (6) exploring gene-gene and genotype-environment interactions; (7) developing improved pemphigus-prone and non-prone animal models that are appropriate for research about the mechanisms that link genotypes to pemphigus. Achieving these goals will demand larger samples of patients and controls and multisite collaborations.

Epidemiology of Pemphigus

“…In both sporadic and endemic (Brazilian) PF, the strongest association was found with HLA DRB1 alleles (∗04 and∗14) and, recently, with DQB1∗05:03 in Chinese Han ( Lombardi et al., 1999 ; Miyagawa et al., 1997 ; Moraes et al., 1997 ; Petzl-Erler, 2020 ; Sun et al., 2019 ).…”

“…In parallel with decreasing sequencing costs, an increasing number of studies based on genome-wide association analyses and selected genetic markers has been published in PV and PF, which were reviewed in Petzl-Erler (2020) and Vodo et al. (2018) .…”

Autoimmune Pemphigus: Latest Advances and Emerging Therapies

“…Knowing the genetic susceptibility in pemphigus may spur further research to better understand the interactions between various genetic susceptibility factors, the role of epigenetics and the functional effects of the identified genetic variants in diseaserelevant cells, and hopefully, ultimately, their influence on response to treatment and severity of disease (Petzl-Erler, 2020).…”

An immunogenetic view of COVID-19

“…A clear example of discordant results due to contrasting allele frequencies between populations comes from HLA in endemic pemphigus foliaceus. Among other differences, the HLA-DRB1 alleles associated with the highest risk in the Brazilian population of predominantly European ancestry are DRB1*01:02 and *04:04 , but in Native Americans, highest risk is associated with DRB1*04:04 only, because DRB1*01:02 is not present ( Petzl-Erler, 2020 ). Thus, the analysis of non-Europeans and admixed populations is urgently needed to identify the COVID-19 causal variants and to evaluate their impact on COVID-19 in worldwide populations.…”