Vecellio Matteo, Rodolfi Stefano, Selmi Carlo
Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom.
Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy.
Semin Immunol. 2021 Dec;58:101665. doi: 10.1016/j.smim.2022.101665. Epub 2022 Oct 26.
Psoriatic Arthritis (PsA) is a complex polygenic inflammatory disease showing a variable musculoskeletal involvement in patients with skin psoriasis. PsA coexist in 25-40 % of patients with the dermatological manifestations, but PsA may also predate the appearance of psoriasis. Nonetheless, the immunopathogenesis of psoriasis and PsA manifest significant similarities, with a major role of the individual susceptibility in both cases. Genome wide association studies (GWAS) identified several genes/loci associated with the risk to develop PsA, both dependent and independent of psoriasis. The major challenge is thus represented by the need to translate the identification of functional polymorphisms and other genetics findings into biological mechanisms along with the identification of novel putative drug targets. A functional genomics approach aims to increase GWAS power and recent evidence supports the use of a multilayer process, including eQTL, methylome, chromatin conformation analysis and genome editing to discover novel genes that can be affected by disease-associated variants, such as PsA. The available data have considered PsA as a unique homogeneous clinical entity while the clinical experience supports a wide variability of skin and joint manifestations coexisting in diverse patients with different mechanisms underlying the musculoskeletal and dermatological domains. A better discrimination of the patient features is encouraged by the limited data on functional genomics. We provide herein a review of the latest findings on PsA functional genomics highlighting the exciting developments in the field and how these might lead to a better understanding of gene regulation underpinning disease mechanisms and ultimately refine clinical phenotyping.
银屑病关节炎(PsA)是一种复杂的多基因炎症性疾病,在患有皮肤银屑病的患者中表现出不同程度的肌肉骨骼受累。PsA在25%-40%的有皮肤病表现的患者中同时存在,但PsA也可能在银屑病出现之前就已存在。尽管如此,银屑病和PsA的免疫发病机制表现出显著的相似性,个体易感性在这两种情况下都起主要作用。全基因组关联研究(GWAS)确定了几个与发生PsA风险相关的基因/位点,这些基因/位点与银屑病有关或无关。因此,主要挑战在于需要将功能性多态性和其他遗传学发现转化为生物学机制,同时确定新的潜在药物靶点。功能基因组学方法旨在提高GWAS的效能,最近的证据支持使用多层方法,包括表达数量性状基因座(eQTL)、甲基化组、染色质构象分析和基因组编辑,以发现可能受疾病相关变异(如PsA)影响的新基因。现有数据将PsA视为一个独特的同质临床实体,而临床经验表明,在不同患者中,皮肤和关节表现存在很大差异,肌肉骨骼和皮肤领域存在不同的潜在机制。功能基因组学的有限数据促使人们更好地区分患者特征。我们在此综述了PsA功能基因组学的最新发现,突出了该领域令人兴奋的进展,以及这些进展如何有助于更好地理解支撑疾病机制的基因调控,并最终完善临床表型分析。
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