Strong Evidence of a Combination Polymorphism of the Tyrosine Kinase 2 Gene and the Signal Transducer and Activator of Transcription 3 Gene as a DNA-Based Biomarker for Susceptibility to Crohn’s Disease in the Japanese Population

Abstract

Objective An association between susceptibility to inflammatory bowel disease (IBD) and polymorphisms of both the tyrosine kinase 2 gene (TYK2) and the signal transducer and activator of transcription 3 gene (STAT3) was examined in a Japanese population in order to identify the genetic determinants of IBD. Methods The study subjects comprised 112 patients with ulcerative colitis, 83 patients with Crohn's disease (CD), and 200 healthy control subjects. Seven tag single-nucleotide polymorphisms (SNPs) in TYK2 and STAT3 were detected by PCR-restriction fragment length polymorphism. Results The frequencies of a C allele and its homozygous C/C genotype at rs2293152 SNP in STAT3 in CD patients were significantly higher than those in control subjects (P=0.007 and P=0.001, respectively). Furthermore, out of four haplotypes composed of the two tag SNPs (rs280519 and rs2304256) in TYK2, the frequencies of a Hap 1 haplotype and its homozygous Hap 1/Hap1 diplotype were significantly higher in CD patients in comparison to those in control subjects (P=0.023 and P=0.024, respectively). In addition, the presence of both the C/C genotype at rs2293152 SNP in STAT3 and the Hap 1/Hap 1 diplotype of TYK2 independently contributes to the pathogenesis of CD and significantly increases the odds ratio to 7.486 for CD (P=0.0008). Conclusion TYK2 and STAT3 are genetic determinants of CD in the Japanese population. This combination polymorphism may be useful as a new genetic biomarker for the identification of high-risk individuals susceptible to CD.

Lack of association between TYK2 and STAT3 genes and Crohn’s disease in the Malaysian population

“…While the homozygous genotype was absent in our results, this was due to the low frequency of the minor A allele. Similar observations have also been reported in the normal sampling of subjects in various other studies, i.e., Spanish (0.269), Japanese (0.38 and 0.345), Caucasians (0.25), and Malaysians (0.255) (Cunninghame Graham et al, 2007;Sato et al, 2009;Suarez-Gestal et al, 2009;Kyogoku et al, 2009, respectively). TYK2 rs2304256 is essentially a missense polymorphism in exon 8; hence, it is possible that while we did not observe any association with CD in isolation, it could be present on a number of neutrally transmitted low-frequency haplotypes in relation to other TYK2 SNPs.…”

“…The primers used to analyze the STAT3 rs2293152, TYK2 rs280519 and TYK2 rs2304256 SNPs are listed in Table 1 (Sato et al, 2009). The PCR cycling parameters for the 3 product amplifications were set according to PCR conditions described elsewhere (Puah et al, 2007;Chua et al, 2010;Ng et al, 2012).…”

Investigation of IL23R, JAK2, and STAT3 gene polymorphisms and gene–gene interactions in Crohn’s disease and ulcerative colitis in a Turkish population

“…This signal pathway expresses in dendritic cells, macrophages, and T and NK cells intensely. Many important molecules, such as IL23, IL23R, JAK2, Tyk2, and STAT3, found in cell membranes and cytoplasm compose the IL23/IL23R pathway (16,19). The signal pathway activation begins with the binding of IL23 to its own receptor.…”

“…The RT-PCR procedure was completed using the PimerDesign®SNPsig Real-Time PCR mutation detection/allelic discrimination Kit (PrimerDesign Ltd.; Southampton, UK) in accordance with the manufacturer's protocol (23). The rs11209026 (G>A, R381Q) of the IL23R gene, rs10758669 (A>C) of the JAK2 gene, and rs3816769 (T>C), rs2293152 (G>C), rs744166 (C>T), rs957970 (C>T), and rs8074524 (C>T) of the STAT3 gene were examined in the obtained genomic DNA (16,17,(19)(20)(21). The prepared 20 μL PCR solution contained 10 μL PimerDesign®2xPrecision MasterMix, 1 μL Primer/probe mix, 4 μL water not containing ribonuclease and deoxyribonuclease, and 5 μL genomic DNA for each reaction.…”

“…It is thought that the IL23/IL23R signal pathway may play a central role in the pathogenesis of IBD. Though there are studies showing that IL23R, JAK2, and STAT3 cause susceptibility to UC and CD in different ethnic groups, the results are not consistent (6,13,(15)(16)(17)(18)(19)(20)(21). The reason for this discrepancy may be that IBD in different ethnic communities may appear through different predominant mechanisms.…”