Association between the PTPN2 gene and Crohn's Disease: Dissection of potential causal variants

Valerie Marcil, David R. Mack, Vijay Kumar, Christophe Faure, Christopher S. Carlson, Patrick Beaulieu, David Israel, Alfreda Krupoves, Irina Costea, Philippe Lambrette, Guy Grimard, Jinsong Dong, Ernest G. Seidman, Devendra K. Amre, Emile Levy

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1149-1155
Number of pages7
JournalInflammatory Bowel Diseases
Volume19
Issue number6
DOIs
StatePublished - May 2013
Externally publishedYes

Fingerprint

Protein Tyrosine Phosphatases
Crohn Disease
Dissection
Single Nucleotide Polymorphism
Genes
Genome-Wide Association Study
Computer Simulation
Inflammation
Proteins
Linkage Disequilibrium
Introns
Meta-Analysis
Exons
Transcription Factors

Keywords

  • Association
  • Children
  • Crohn's disease
  • Protein
  • PTPN2 gene

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Marcil, V., Mack, D. R., Kumar, V., Faure, C., Carlson, C. S., Beaulieu, P., ... Levy, E. (2013). Association between the PTPN2 gene and Crohn's Disease: Dissection of potential causal variants. Inflammatory Bowel Diseases, 19(6), 1149-1155. https://doi.org/10.1097/MIB.0b013e318280b181

Association between the PTPN2 gene and Crohn's Disease : Dissection of potential causal variants. / Marcil, Valerie; Mack, David R.; Kumar, Vijay; Faure, Christophe; Carlson, Christopher S.; Beaulieu, Patrick; Israel, David; Krupoves, Alfreda; Costea, Irina; Lambrette, Philippe; Grimard, Guy; Dong, Jinsong; Seidman, Ernest G.; Amre, Devendra K.; Levy, Emile.

In: Inflammatory Bowel Diseases, Vol. 19, No. 6, 05.2013, p. 1149-1155.

Research output: Contribution to journalArticle

Marcil, V, Mack, DR, Kumar, V, Faure, C, Carlson, CS, Beaulieu, P, Israel, D, Krupoves, A, Costea, I, Lambrette, P, Grimard, G, Dong, J, Seidman, EG, Amre, DK & Levy, E 2013, 'Association between the PTPN2 gene and Crohn's Disease: Dissection of potential causal variants', Inflammatory Bowel Diseases, vol. 19, no. 6, pp. 1149-1155. https://doi.org/10.1097/MIB.0b013e318280b181
Marcil, Valerie ; Mack, David R. ; Kumar, Vijay ; Faure, Christophe ; Carlson, Christopher S. ; Beaulieu, Patrick ; Israel, David ; Krupoves, Alfreda ; Costea, Irina ; Lambrette, Philippe ; Grimard, Guy ; Dong, Jinsong ; Seidman, Ernest G. ; Amre, Devendra K. ; Levy, Emile. / Association between the PTPN2 gene and Crohn's Disease : Dissection of potential causal variants. In: Inflammatory Bowel Diseases. 2013 ; Vol. 19, No. 6. pp. 1149-1155.
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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.",
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T1 - Association between the PTPN2 gene and Crohn's Disease

T2 - Dissection of potential causal variants

AU - Marcil, Valerie

AU - Mack, David R.

AU - Kumar, Vijay

AU - Faure, Christophe

AU - Carlson, Christopher S.

AU - Beaulieu, Patrick

AU - Israel, David

AU - Krupoves, Alfreda

AU - Costea, Irina

AU - Lambrette, Philippe

AU - Grimard, Guy

AU - Dong, Jinsong

AU - Seidman, Ernest G.

AU - Amre, Devendra K.

AU - Levy, Emile

PY - 2013/5

Y1 - 2013/5

N2 - 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.

AB - 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.

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