Multifaceted analysis of cross-tissue transcriptomes reveals phenotype–endotype associations in atopic dermatitis

Author:

Sekita AikoORCID,Kawasaki Hiroshi,Fukushima-Nomura AyanoORCID,Yashiro Kiyoshi,Tanese Keiji,Toshima Susumu,Ashizaki Koichi,Miyai TomohiroORCID,Yazaki JunshiORCID,Kobayashi Atsuo,Namba ShinichiORCID,Naito TatsuhikoORCID,Wang Qingbo S.,Kawakami EiryoORCID,Seita JunORCID,Ohara OsamuORCID,Sakurada Kazuhiro,Okada YukinoriORCID,Amagai MasayukiORCID,Koseki HaruhikoORCID

Abstract

AbstractAtopic dermatitis (AD) is a skin disease that is heterogeneous both in terms of clinical manifestations and molecular profiles. It is increasingly recognized that AD is a systemic rather than a local disease and should be assessed in the context of whole-body pathophysiology. Here we show, via integrated RNA-sequencing of skin tissue and peripheral blood mononuclear cell (PBMC) samples along with clinical data from 115 AD patients and 14 matched healthy controls, that specific clinical presentations associate with matching differential molecular signatures. We establish a regression model based on transcriptome modules identified in weighted gene co-expression network analysis to extract molecular features associated with detailed clinical phenotypes of AD. The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures. We further apply the regression model to a longitudinal dataset of 30 AD patients for personalized monitoring, highlighting patient heterogeneity in disease trajectories. The longitudinal features of blood tests and PBMC transcriptome modules identify three patient clusters which are aligned with clinical severity and reflect treatment history. Our approach thus serves as a framework for effective clinical investigation to gain a holistic view on the pathophysiology of complex human diseases.

Funder

Japan Agency for Medical Research and Development

MEXT | Japan Science and Technology Agency

MEXT | Japan Society for the Promotion of Science

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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