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.

中文翻译：

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超越 HLA 多态性：天疱疮遗传易感性的复杂模式

摘要 天疱疮是一组发病率很高的自身免疫性大疱性皮肤病。至于其他多因素自身免疫性疾病，环境因素可能会引发遗传易感个体的疾病。本综述的目的是总结可能影响寻常型天疱疮和落叶型天疱疮（地方性和散发型）的易感性和发病机制的遗传变异的知识状态，以比较和讨论所报告关联的可能含义，并为新的研究计划提出建议。对于大多数导致疾病易感性的多态性，了解遗传变异如何转化为致病机制和表型仍然是一个谜。然而，遗传研究通过产生可检验的假设为该领域的进一步发展奠定了坚实的基础。目前，结果对疾病预防和预后、药物开发和临床实践的影响仍然有限，尽管未来应用的前景使患者受益是令人鼓舞的。继续推进我们对遗传变异对天疱疮影响的理解的建议包括这些部分重叠的目标：（1）通过其对顺式调节 DNA 的核苷酸序列的影响，查询遗传变异对基因表达调节的功能影响诸如启动子和增强子之类的元件，RNA 的剪接，调节 RNA 和蛋白质的结构，这些调节分子与调节 DNA 元件的结合，和表观遗传标记的改变；(2) 鉴定与天疱疮发病机制有关的关键细胞类型和细胞状态并探索其功能基因组；(3) 整合结构和功能基因组学数据；(4) 进行疾病进展纵向研究，揭示遗传和表观遗传变异与中间疾病表型之间的因果关系；(5) 了解遗传和表观遗传变异对治疗反应和疾病严重程度的影响；(6) 探索基因-基因和基因型-环境的相互作用；(7) 开发改进的天疱疮易发和非天疱疮动物模型，适用于研究将基因型与天疱疮联系起来的机制。实现这些目标将需要更多的患者和对照样本以及多站点合作。