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1、Genetic analysis of an allergic rhinitis cohort reveals an intercellular epistasis between FAM134B and CD39 Rossella Melchiotti1,2, Email: rossella_melchiottiimmunol.a-star.edu.sg Kia Joo Puan1, Email: puan_kia_jooimmunol.a-star.edu.sg Anand Kumar Andiappan1, Email: anand_andiappanimmunol.a-star.edu
2、.sg Tuang Yeow Poh1 Email: poh_tuang_yeowimmunol.a-star.edu.sg Mireille Starke1 Email: Li Zhuang1 Email: lydia_zhuangimmunol.a-star.edu.sg Kerstin Petsch1 Email: kerstin.petschmdc-berlin.de Tuck Siong Lai1 Email: adrian_lai_ Fook Tim Chew3 Email: dbscftnus.edu.sg Anis Larbi1 Email: anis_larbiimmuno
3、l.a-star.edu.sg De Yun Wang4* * Corresponding author Email: entwdynus.edu.sg Michael Poidinger1* * Corresponding author Email: michael_poidingerimmunol.a-star.edu.sg Olaf Rotzschke1* * Corresponding author Email: olaf_rotzschkeimmunol.a-star.edu.sg 1 SIgN (Singapore Immunology Network), A*STAR (Agen
4、cy for Science, Technology and Research), Singapore 138648, Singapore 2 Doctoral School in Translational and Molecular Medicine (DIMET), University of Milano-Bicocca, Milan 20126, Italy 3 Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore 4 Department of
5、 Otolaryngology, National University of Singapore, Singapore 119228, Singapore Equal contributors. Abstract Background Extracellular ATP is a pro-inflammatory molecule released by damaged cells. Regulatory T cells (Treg) can suppress inflammation by hydrolysing this molecule via ectonucleoside triph
6、osphate diphosphohydrolase 1 (ENTPD1), also termed as CD39. Multiple studies have reported differences in CD39+ Treg percentages in diseases such as multiple sclerosis, Hepatitis B and HIV-1. In addition, CD39 polymorphisms have been implicated in immune- phenotypes such as susceptibility to inflamm
7、atory bowel disease and AIDS progression. However none of the studies published so far has linked disease-associated variants with differences in CD39 Treg surface expression. This study aims at identifying variants affecting CD39 expression on Treg and at evaluating their association with allergic
8、rhinitis, a disease characterized by a strong Treg involvement. Methods Cohorts consisting of individuals of different ethnicities were employed to identify any association of CD39 variants to surface expression. Significant variant(s) were tested for disease association in a published GWAS cohort b
9、y one-locus and two-locus genetic analyses based on logistic models. Further functional characterization was performed using existing microarray data and quantitative RT-PCR on sorted cells. Results Our study shows that rs7071836, a promoter SNP in the CD39 gene region, affects the cell surface expr
10、ession on Treg cells but not on other CD39+ leukocyte subsets. Epistasis analysis revealed that, in conjunction with a SNP upstream of the FAM134B gene (rs257174), it increased the risk of allergic rhinitis (P = 1.98 106). As a promoter SNP, rs257174 controlled the expression of the gene in monocyte
11、s but, notably, not in Treg cells. Whole blood transcriptome data of three large cohorts indicated an inverse relation in the expression of the two proteins. While this observation was in line with the epistasis data, it also implied that a functional link must exist. Exposure of monocytes to extrac
12、ellular ATP resulted in an up-regulation of FAM134B gene expression, suggesting that extracellular ATP released from damaged cells represents the connection for the biological interaction of CD39 on Treg cells with FAM134B on monocytes. Conclusions The interplay between promoter SNPs of CD39 and FAM
13、134B results in an intercellular epistasis which influences the risk of a complex inflammatory disease. Keywords Epistasis, Treg, Monocyte, eQTLs, Allergic Rhinitis Background Allergic Rhinitis (AR) is a common airway disease where allergen exposure triggers an IgE- mediated immune response. The typ
14、ical symptoms include nasal itchiness, rhinorrhea, sneezing and progressive blockage of the inflamed nasal passages 1. The disease is driven by a complex interplay of various leukocytes, including mast cells, eosinophils and basophils but also CD4+ T cells, IgE-producing B cells and dendritic cells.
15、 Th2 cytokines such as IL-4, IL-5 and IL-13 drive IgE production, promote eosinophil infiltration to the nasal mucosa, and stimulate mast cell release of key vasoactive mediators such as histamine 2-4. In this context also monocytes are important effectors and regulators of inflammation 5. While pro
16、-inflammatory monocytes can fuel the allergic reaction by releasing cytokines such as TNF- and IL-6, they can be converted into anti-inflammatory monocytes to dampen the reaction 6. Central to the prevention or attenuation of pro-inflammatory immune responses are CD4+ Foxp3+ T regulatory cells (Treg). They can inhibit the proliferation of CD4+ effector T cells and impair the produc
