We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY.
Here, we demonstrate increased PTPN2 expression in CD intestinal biopsy specimens and that the proinflammatory cytokine interferon (IFN)-gamma increases PTPN2 expression and activity in IEC.
PTPN2 (rs2542151) was only associated in the smoking CD cohort (P=0.041), and not in the entire cohort (P=0.23) or in the non-smoking CD cohort (P=0.80).
Allelic association analysis (two-tailed) showed that three of the five targeted SNPs were significantly associated with overall susceptibility for CD (ZNF365, r10995271, P = 0.001; PTPN2, rs1893217, P = 0.005; STAT3, rs744166, P = 0.01).
In this sample, we were able to confirm an association between CD and PTPN2 (genotypic P = 0.019 and allelic P = 0.011), and phenotypic analysis showed an association of this SNP with late age at first diagnosis, inflammatory and penetrating CD behaviour, requirement of bowel resection and being a smoker at diagnosis.
Though samples from patients with active ulcerative colitis (UC) revealed more PTPN2 protein than non-IBD patients and patients with UC in remission, their PTPN2 expression was lower than in active CD.
A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease.
Colon-only CD (n = 228) was compared with healthy controls: three of six UC SNPs (in MST1, HLA-DRA, and IL-23R) and 11 of 34 CD SNPs: in IRGM, NOD2 (rs2066845), CCNY, MST1, IL23R, PTPN22, C11orf30, ZNF365, PTPN2, PSMG1, and rs1456893 were significantly associated.
Recent studies associated variants within the gene loci, encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2), and autophagy genes, such as autophagy-related 16-like 1 (ATG16L1), with chronic inflammatory disorders, such as Crohn's disease (CD).
These results suggest that PTPN2 may have an important role in CD pathogenesis and may represent a potential diagnostic and therapeutic target for IBD.
The study indicates that IL23R-rs11805303 and PTPN2-rs2542151 might contribute to the development of UC and NOD2-P268S might be involved in the etiology of CD in the Chinese Han population.
Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p = 0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p = 4.68×10⁻³) in UC.
These data identify an important functional role for PTPN2 as a protector of the intestinal epithelial barrier and provide clues as to how PTPN2 mutations may contribute to the pathophysiology of CD.
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 PTPN2CD-associated SNPs.
We confirmed 6 previously reported loci in Caucasian: GPR35 at 2q37 (rs3749172; P = 5.30 × 10, odds ratio [OR] = 1.45), ZNF365 at 10q21 (rs224143; P = 2.20 × 10, OR = 1.38), ZMIZ1 at 10q22 (rs1250569; P = 3.05 × 10, OR = 1.30), NKX2-3 at 10q24 (rs4409764; P = 7.93 × 10, OR = 1.32), PTPN2 at 18p11 (rs514000; P = 9.00 × 10, OR = 1.33), and USP25 at 21q11 (rs2823256; P = 2.49 × 10, OR = 1.35), bringing the number of known CD loci (including 3 in the HLA) in Koreans to 15.
Our data demonstrate that dysfunction of PTPN2 results in aberrant T-cell differentiation and intestinal dysbiosis similar to those observed in human CD.