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.

摘要 天疱疮（Pemphigus）是一类可导致严重发病负担的自身免疫性大疱性皮肤病。与其他多因素自身免疫性疾病类似，环境因素可在遗传易感个体中诱发该病。
本综述旨在梳理目前关于可能影响寻常型天疱疮（pemphigus vulgaris）与落叶型天疱疮（pemphigus foliaceus，含地方性与散发性亚型）易感性及发病机制的遗传变异研究现状，对比并探讨已报道的关联信号的潜在意义，并为新的研究方向提出建议。
对于绝大多数参与疾病易感性的遗传多态性而言，阐明遗传变异如何转化为致病机制与表型仍是未解之谜。不过，遗传研究通过生成可验证的假说，为本领域的后续发展奠定了坚实基础。尽管未来面向患者的应用前景令人振奋，但目前相关研究结果对疾病预防、预后评估、药物研发及临床实践的影响仍较为有限。
为推动我们对遗传变异在天疱疮发病中作用的认知，可遵循以下部分存在重叠的研究目标：
1. 解析遗传变异通过以下途径对基因表达调控产生的功能效应：改变顺式调控DNA元件（cis regulatory DNA elements，如启动子（promoters）与增强子（enhancers））的核苷酸序列、影响RNA剪接过程、调控RNA与蛋白质的结构、改变这些调控分子与调控DNA元件的结合能力，以及修饰表观遗传标记（epigenetic marks）；
2. 鉴定参与天疱疮发病机制的关键细胞类型与细胞状态，并解析其功能基因组；
3. 整合结构基因组学与功能基因组学数据；
4. 开展疾病进展纵向研究（longitudinal studies），以阐明遗传与表观遗传变异与疾病中间表型之间的因果关联；
5. 明确遗传与表观遗传变异对疾病治疗应答及病情严重程度的影响；
6. 探究基因-基因互作与基因型-环境互作关系；
7. 构建更优化的天疱疮易感与非易感动物模型，以适配基因型与天疱疮发病关联机制的相关研究。
达成上述研究目标需要纳入更大规模的患者与对照样本，并开展多中心合作（multisite collaborations）。