title: Association between the PTPN2 gene and Crohn's disease: dissection of potential causal variants.
abstract: BACKGROUND
  Although genome-wide association studies (GWAS) and subsequent meta-analyses have confirmed associations between the PTPN2 (protein tyrosine phosphatase, nonreceptor type 2) gene and Crohn's disease (CD), the potential causal variants remain unidentified. We aimed to dissect potential causal CD-associated PTPN2 variants, assess their functional significance, and relate PTPN2 protein expression with inflammation in CD.
  
  
  METHODS
  A 3-stage study was carried out. In stage 1, we genotyped tagging single nucleotide polymorphisms (tag-SNPs) in the PTPN2 gene in a sample of patients with CD (<20 years, n = 556) and controls (n = 602). In stage 2, we resequenced the putative promoter, target exons and introns in the PTPN2 gene, and examined associations with high-frequency variants with CD in the stage 1 cohort. In stage 3 we studied the relationship between PTPN2 protein expression and mucosal inflammation and carried out in silico analyses to study the functional characteristics of the PTPN2 CD-associated SNPs.
  
  
  RESULTS
  In stage 1, we observed associations between 5 intronic SNPs and CD including rs1893217 (P = 2 × 10⁻⁴), the SNP that is in perfect linkage disequilibrium with the lead genome-wide association studies SNP rs2542151. Resequencing revealed 2 known promoter polymorphisms. No associations between these promoter SNPs and CD were evident. In silico analyses revealed that the 5 associated intronic SNPs influenced PTPN2 expression and binding to important transcription factors. PTPN2 protein was overexpressed in inflamed intestinal tissues of patients with CD.
  
  
  CONCLUSIONS
  Our findings suggest that noncoding variation in the PTPN2 gene may represent the causal variations influencing susceptibility for CD.
authors.affiliation: Research Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Valerie
authors.initials: V
authors.lastname: Marcil
authors.forename: David R
authors.initials: DR
authors.lastname: Mack
authors.forename: Vijay
authors.initials: V
authors.lastname: Kumar
authors.forename: Christophe
authors.initials: C
authors.lastname: Faure
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Patrick
authors.initials: P
authors.lastname: Beaulieu
authors.forename: David
authors.initials: D
authors.lastname: Israel
authors.forename: Alfreda
authors.initials: A
authors.lastname: Krupoves
authors.forename: Irina
authors.initials: I
authors.lastname: Costea
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambrette
authors.forename: Guy
authors.initials: G
authors.lastname: Grimard
authors.forename: Jinsong
authors.initials: J
authors.lastname: Dong
authors.forename: Ernest G
authors.initials: EG
authors.lastname: Seidman
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Amre
authors.forename: Emile
authors.initials: E
authors.lastname: Levy
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000032:analysis*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D003424:Crohn Disease / Q000209:etiology*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D015810:Linkage Disequilibrium; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
chemical_list: D015415:Biomarkers; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2