title: Genetic analysis of an allergic rhinitis cohort reveals an intercellular epistasis between FAM134B and CD39.
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.
authors: Rossella
authors: R
authors: Melchiotti
authors: Kia Joo
authors: KJ
authors: Puan
authors: Anand Kumar
authors: AK
authors: Andiappan
authors: Tuang Yeow
authors: TY
authors: Poh
authors: Mireille
authors: M
authors: Starke
authors: Li
authors: L
authors: Zhuang
authors: Kerstin
authors: K
authors: Petsch
authors: Tuck Siong
authors: TS
authors: Lai
authors: Fook Tim
authors: FT
authors: Chew
authors: Anis
authors: A
authors: Larbi
authors: SIgN (Singapore Immunology Network), A*STAR (Agency for Science, Technology and Research), Singapore 138648, Singapore. entwdy@nus.edu.sg.
authors: De Yun
authors: de Y
authors: Wang
authors: Michael
authors: M
authors: Poidinger
authors: Olaf
authors: O
authors: Rotzschke
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D001081:Apyrase / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D014644:Genetic Variation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009000:Monocytes / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015203:Reproducibility of Results; D065631:Rhinitis, Allergic; D012221:Rhinitis, Allergic, Perennial / Q000235:genetics* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D015703:Antigens, CD; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C522691:RETREG1 protein, human; D001081:Apyrase; C067869:CD39 antigen