Association of the protein-tyrosine phosphatase nonreceptor type substrate 1 (PTPNS1) gene with inflammatory bowel disease.

To the Editor: Genetic risk factors identified for inflammatory bowel disease (IBD) collectively only explain around 10%–20% of the heritability of ulcerative colitis (UC) and Crohn’s disease (CD). Therefore, it seems increasingly likely that the missing heritability of IBD will be explained by gene–gene interactions, gene–environment interactions, structurally complex copy number polymorphisms which are poorly tagged by single nucleotide polymorphisms (SNPs), and loci of very modest effect size. A pooled genome-wide association study (GWAS) of 252 unrelated New Zealand (NZ) Caucasians with CD and 187 controls has provided preliminary evidence of association of PTPNS1 SNP rs6045210 with CD (P 1⁄4 0.03, odds ratio [OR] 1⁄4 0.52, 95% confidence interval [CI]: 0.28–0.94). PTPNS1 (also known as: SIRPalpha, SHPS-1, BIT, MFR, CD172a, MYD1, or p84) is a paired cell surface receptor that interacts with the ligand CD47 to control ‘‘homeostatic’’ innate immune effector functions, such as host cell phagocytosis. This protein is especially abundant on the surface of macrophages and dendritic cells (DCs). Moreover, PTPNS1expressing DCs within the lamina propria have recently been demonstrated to promote Th17-biased colitis in a murine model. We hypothesize that PTPNS1 may be a novel risk locus for IBD, previously undetected, due to its small effect size. The aim of this study was to validate and replicate the initial association of PTPNS1 with CD and extend association testing to include UC. The validation sample set comprised 492 independent New Zealand Caucasians (CD n 1⁄4 206, controls n 1⁄4 286) and the two replication sample sets comprised 2133 Dutch Caucasians (CD n 1⁄4 933, UC n 1⁄4 664, controls n 1⁄4 536) and 885 Spanish Caucasians (CD n 1⁄4 264, UC n 1⁄4 246, controls n 1⁄4 375). Diagnosis of CD or UC was based on standard clinical, radiologic, endoscopic, and histopathologic criteria for all sample sets. DNA was collected from peripheral blood samples by sodium chloride extraction and genotyping for the PTPNS1 SNP rs6045210 was performed using a predesigned TaqMan SNP genotyping assay (ID: C__27046712_10, Applied Biosystems, Foster City, CA). No deviations from Hardy–Weinberg Equilibrium were detected (all P-values >0.05). Within the NZ GWAS and validation sample sets the minor allele (C)-containing genotypes of rs6045210 were significantly lower in CD patients than in controls (Pcombined 1⁄4 0.002, OR 1⁄4 0.54, 95% CI: 0.36–0.80) (Table 1). A modest protective effect of the TC and CC genotypes was also detected in NZ UC patients (P 1⁄4 0.047, OR 1⁄4 0.69, 95% CI: 0.48–0.99) (Table 1). No association of PTPNS1 with CD was observed in either replication sample set (PDutch 1⁄4 0.71 and PSpanish 1⁄4 0.23; Table 1). Similarly, PTPNS1 was not associated with UC in the Spanish sample set (P 1⁄4 0.79), but a trend towards significance was observed in Dutch UC patients (P 1⁄4 0.10, OR 1⁄4 0.76, 95% CI: 0.55–1.06) (Table 1). Combined analysis of the NZ, Dutch, and Spanish sample sets with genotypes imputed from the Wellcome Trust Case Control Consortium (WTCCC) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) datasets revealed that the rs6045210 CC and CT genotypes conferred significant protection against UC (P 1⁄4 0.002, OR 1⁄4 0.73, 95% CI: 0.60–0.89) and IBD (P 1⁄4 0.007, OR 1⁄4 0.87, 95% CI:0.79–0.96), and a nonsignificant protective effect against CD (P 1⁄4 0.092, OR 1⁄4 0.85, 95% CI: 0.70–1.03) (Table 1). PTPNS1 expression and subsequent ligation to the glycoprotein CD47 is crucial to prevent phagocytosis of host cells by macrophages. More recently, PTPNS1 has also been shown to be important in the migration of Langerhans cells, monocytes, and neutrophils; the production of cytokines by immune cells; generation of nitric oxide by macrophages; and the regulation of lipopolysaccharide (LPS)-induced activation of Tolllike receptors. However, the first evidence that PTPNS1 may directly alter susceptibility to inflammatory diseases has come from murine models. In mice expressing a mutant form of PTPNS1 on CD11cþ, DCs were found to be highly resistant to the development of experimental autoimmune encephalomyelitis (a model of multiple sclerosis) compared to wildtype mice. Furthermore, in another murine model intestinal CD103 DCs expressing wildtype PTPNS1 were found, along with CD47, to be crucial for Th-17 response and subsequent development of experimental colitis. While the evidence of association of PTPNS1 with IBD is preliminary, the role of DC-expressed PTPNS1 in driving TH17-biased responses and colitis makes this gene a candidate worthy of further investigation.