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Open Access Research article

Genetic analysis of an allergic rhinitis cohort reveals an intercellular epistasis between FAM134B and CD39

Rossella Melchiotti12, Kia Joo Puan1, Anand Kumar Andiappan1, Tuang Yeow Poh1, Mireille Starke1, Li Zhuang1, Kerstin Petsch1, Tuck Siong Lai1, Fook Tim Chew3, Anis Larbi1, De Yun Wang4*, Michael Poidinger1* and Olaf Rotzschke1*

Author Affiliations

1 SIgN (Singapore Immunology Network), A*STAR (Agency 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 Otolaryngology, National University of Singapore, Singapore 119228, Singapore

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BMC Medical Genetics 2014, 15:73  doi:10.1186/1471-2350-15-73

Published: 27 June 2014

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 triphosphate 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 inflammatory 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 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 by 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 expression 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 × 10-6). As a promoter SNP, rs257174 controlled the expression of the gene in monocytes 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 extracellular 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 FAM134B results in an intercellular epistasis which influences the risk of a complex inflammatory disease.

Keywords:
Epistasis; Treg; Monocyte; eQTLs; Allergic rhinitis