Ji-In Yu

Identification of single nucleotide polymorphisms in the TNFRSF17 gene and their association with gastrointestinal disorders

TNFRSF17 is preferentially expressed in mature B lymphocytes, and may be important for the development of B cells. TNFRSF17 is selected as a candidate susceptibility gene to IBD pathogenesis by our cDNA microarray analysis, and we showed the specific expression of TNFRSF17 in resting and activated CD19+ cells obtained from human blood. We identified four SNPs (g-1729G>A, g.2295T>C, g.2445G>A and g.2493G>A) and one variation site (g.894delT) in the TNFRSF17 gene using direct sequencing analysis. In addition, the association of the genotype and allelic frequencies of these SNPs was studied in healthy controls and in patients with ulcerative colitis (UC) or irritable bowel syndrome (IBS). Although, the genotype and allelic frequencies of these SNPs, in the UC and IBS patients, were not significantly different from those in the healthy controls, the distribution of the AAG, GGA, AGG and AAA haplotypes, of the SNPs (g.-1729G>A, g.2445G> A and g.2493G>A) associated with the TNFRSF17 gene, in the UC patients, were notably different from those of the healthy controls (P = 0.002, 0.002, 4.7E-4 and 3.3E-6, respectively). Moreover, the frequencies of the AAG, AGG, GAG and GAA haplotypes were significantly different in the IBS patients compared to the healthy controls (P = 4.2E-5, 4.4E-17, 1.8E-22 and 1.6E-10, respectively). These results suggest that the haplotypes of the TNFRSF17 polymorphisms might be associated with UC and IBS susceptibility.

Identifying Polymorphisms in IL-31 and Their Association with Susceptibility to Asthma.

Background Interleukin 31 (IL-31) is a T helper type 2 effector cytokine that plays an important role in the pathogenesis of atopic and allergic diseases. IL-31 may be involved in promoting allergic inflammation and in inducing airway epithelial responses such as allergic asthma. Methods Single-base extension analysis was used to detect the genotypes of IL-31 single nucleotide polymorphisms (SNPs), and we compared the genotype and allele frequencies of the IL-31 SNPs between patients with asthma and healthy controls. Results There were no significant differences in the genotype and allele frequencies of the IL-31 SNPs between patients with asthma and healthy controls. Furthermore we compared the genotype and allele frequencies of IL-31 SNPs between patients with atopic asthma, those with non-atopic asthma and healthy controls. This showed that the SNPs were not associated with the susceptibility to atopic asthma. There were no significant differences in the haplotype frequencies of IL-31 SNPs between patients with asthma and healthy controls. In patients with asthma, the IL-31 SNPs were significantly correlated with total serum levels of IgE (p=0.035). Conclusions Our results indicate that, the IL-31 SNPs may be associated with IgE production in patients with asthma.

Polymorphisms of interleukin-31 are associated with anti-CCP levels in females with rheumatoid arthritis.

Cytokines play important roles in a wide range of different cell types, tissues and organs. Interleukin-31 (IL-31) is a member of the IL-6 family of cytokines. IL-31 is a T helper type 2 (Th2) effecter cytokine that plays an important role in atopic and allergic diseases. It was found that genotype and allele frequencies of the IL-31 SNPs in rheumatoid arthritis (RA) patients were not significantly different from those in the healthy controls. The haplotype frequencies of IL-31 SNPs were also not significantly different between the RA patients and the healthy controls. The g.-1066G>A, g.586C>A and g.1449C>G polymorphisms of IL-31 were significantly associated with the anti-CCP levels in the female RA patients (P = 0.010, 0.012 and 0.025, respectively). The results indicate that in RA patients, IL-31 SNPs may play a role in anti-CCP production, and suggest that SNPs in the IL-31 gene could be associated with susceptibility to RA. RA is one of the most common autoimmune diseases worldwide and is characterized by the inflammation of synovial tissues and the formation of rheumatoid pannus, which is capable of eroding adjacent cartilage and bone and cause subsequent joint destruction (Goldring and Gravallese 2000). RA comes about through a complex interaction betweenmultiple genetic and environmental factors (Gregersen 1999). The activated T helper (Th) cells during the developing stage are differentiated phenotypically and functionally into two distinct types of cells, Th1 and Th2 (Abbas et al. 1996). Th1 cells produce cytokines such as interferonγ (IFN-γ ), IL-12 and the cytotoxic factor lymphotoxin. They are commonly associated with cell-mediated immune

Identification of the polymorphisms in IFITM1 gene and their association in a Korean population with ulcerative colitis

Abstract Interferon inducible transmembrane protein (IFITM) family genes have been implicated in several cellular processes such as the homotypic cell adhesion functions of IFNs and cellular anti-proliferative activities. We previously showed that the IFITM3 single nucleotide polymorphisms (SNPs) associated with susceptibility to ulcerative colitis (UC). The present study aimed to investigate whether the polymorphisms in the IFITM1 gene are associated with susceptibility to UC. We also evaluated the expression levels in the putative functional promoter polymorphisms to determine the change of their activity. Gene expression profiles in the tissues obtained from human digestive tracts by RT-PCR, and the possible variation sites and SNPs of IFITM1 were identified by direct sequencing method. Genotype analysis in the IFITM1 SNPs was performed by high resolution melting and TaqMan probe analysis, and the haplotype frequencies of IFITM1 SNPs for multiple loci were estimated using the expectation maximization (EM) algorithm. The expression levels in the putative functional promoter polymorphisms were evaluated by performing a luciferase reporter assay. We identified two SNPs and two variation sites, g.-1920G>A (rs77537847), g.-1547delA (novel) and g.-416C>G (rs11246062) in the promoter region, and g.364delA (rs200576757) in intron 1. The genotype and allele frequencies of the g.-1920G>A polymorphism of IFITM1 gene in the UC patients were significantly different from those of the healthy controls (P =0.002 and 0.042, respectively). These results suggest that the g.-1920G>A polymorphism in IFITM1 may be associated with susceptibility to UC.

EED gene polymorphism in patients with colorectal cancer.

Background Our previous work indicated that, first, the embryonic ectoderm development (EED) gene is a candidate gene associated with the pathogenesis of ulcerative colitis (UC) and, second, that the haplotypes of the EED polymorphism are one of the markers for UC susceptibility. The risk of developing colorectal cancer (CRC) increases in patients with inflammatory bowel disease. Aim The present study aimed at determining the association between polymorphisms in the EED gene and CRC. Methods Genotype analysis of EED single nucleotide polymorphisms (SNPs) was performed with high-resolution melting analysis, and the genotype and allele frequencies of the EED SNPs were compared between CRC patients and healthy controls. The haplotype frequencies of EED for multiple loci were estimated using the expectation maximization (EM) algorithm. Results Our study had a power of 76.6% at a 0.05 significance level. Genotype and allele frequencies of the SNPs and haplotype frequencies of the EED gene in CRC patients were not significantly different from those in healthy controls. Only the allele frequency of g.-1850G>C in the rectal cancer (RC) patient group was significantly different from that of the control group (p=0.04). Similarly, the genotype and allelic frequencies of the EED SNPs for either tumor site (left or right) or tumor stage were not significantly different from those in healthy controls. However, our data show an association between the g.-993G>C polymorphism in the EED gene and the presence of lymph node metastasis in CRC. Conclusions These results suggest that the SNPs of the EED gene might not be associated with susceptibility to CRC. However, this study shows that the allele frequency of g.-1850G>C in the RC patient group was significantly different from that in the control group (p=0.04) and that g.-993G>C may play a role in the lymph node metastatic process of CRC.

TSLPR gene polymorphism is associated with systemic lupus erythematosus in the Korean population

Human thymic stromal lymphopoietin receptor (TSLPR) was identified from T lymphocytes and dendritic cells, and is believed to play an important role in the development of inflammatory and allergic responses. We previously identified 11 single-nucleotide polymorphisms (SNPs) and 2 variation sites in the TSLPR gene, and showed that SNPs in the TSLPR gene are associated with susceptibility to atopic asthma in the Korean population. The present study aimed to investigate whether polymorphisms in the TSLPR gene are associated with systematic lupus erythematosus (SLE). The genotype and allele frequencies of the g.33G>C SNP of the TSLPR gene in SLE patients were significantly different from those of the control group (P = 0.005). Additional analysis showed that the genotype and allele frequencies of the g.33G>C of the TSLPR gene were suggestively associated with female SLE patients. We also investigated the correlation between SNPs in the TSLPR gene and the total serum levels of anti-nuclear antibodies (ANA) in SLE patients. The g.21884G>A SNP of the TSLPR gene in SLE patients showed a significant association with ANA levels (P = 0.014). Our results suggest that SNPs in the TSLPR gene could be associated with susceptibility to SLE in the Korean population.

Associations of IFITM3 haplotypes with rheumatoid arthritis in a Korean population

Interferons (IFNs) play important roles in tumor pathogenesis by controlling apoptosis and through cellular anti-proliferative and differentiation activities. Interferon inducible transmembrane protein (IFITM) family genes were first discovered in interferon-treated neuroblastoma cells. IFITM3 is a member of the IFITM family, and has been described as a key player in the specification of germ cell fate. We have previously identified 7 single nucleotide polymorphisms (SNPs) and multiple variation regions in the IFITM3 gene and have suggested that IFITM3 polymorphisms are associated with a susceptibility to ulcerative colitis (UC). The present study investigates whether the IFITM3 SNPs g.-204T>G, g.-175T>C, and g.42C>T are associated with rheumatoid arthritis (RA). Although, the genotype and allelic frequencies of these SNPs in the RA patients were not different from those in the healthy control group, the distribution of the major haplotypes (GTC, TCT and TTT) of the IFITM3 SNPs in RA patients were significantly different from those in the healthy control group (P = 5.34E-12, 1.47E-5 and 1.51E-18, respectively). Our results strongly suggest that the haplotypes of the IFITM3 polymorphisms may be associated with a susceptibility to RA.

Association of Thymic Stromal Lymphopoietin Receptor (TSLPR) Polymorphisms with the Susceptibility of Rheumatoid Arthritis in a Korean Population

Human thymic stromal lymphopoietin receptor (TSLPR) might play an important role in the development of inflammatory and allergic responses. We previously identified eleven single nucleotide polymorphisms (SNPs) and two variation sites in the TSLPR gene and showed that all the SNPs of the TSLPR gene are associated with susceptibility to atopic asthma. The present study aimed to investigate whether the TSLPR gene SNPs are associated with susceptibility to rheumatoid arthritis (RA). We compared the genotype and the allele frequencies of the TSLPR SNPs in 457 RA patients and 570 healthy controls. The genotype and the allele frequencies of the TSLPR gene SNPs in the RA patients were not significantly different from the respective frequencies of the healthy controls. Additional analysis showed that the genotype and the allele frequencies of the TSLPR gene SNPs did not appear to be associated with RA in female RA patients. The TSLPR gene SNPs in the RA patients did not affect the production of rheumatoid factor (RF) and antisynthetic cyclic citrullinated peptide (CCP). Our results suggest that the TSLPR gene SNPs are not associated with susceptibility to RA in the Korean population.

Thymic Stromal Lymphopoietin (TSLP) Gene Polymorphisms are not Associated with Rheumatoid Arthritis in a Korean Population

Thymic stromal lymphopoietin (TSLP) is a novel IL-7-like hematopoietic cytokine. Human TSLP is produced by epithelial cells, stromal cells, and mast cells. The TSLP gene is highly expressed in synovial fluid specimens derived from rheumatoid arthritis (RA) patients. We previously identified four single nucleotide polymorphisms (SNPs) and one variation site in human TSLP gene. In this study, we analyzed the genotypic and allelic frequencies of the TSLP SNPs between RA patients and healthy controls. We also investigated the relationships between SNP genotypes and the RF levels and anti-synthetic cyclic citrullinated peptide (CCP) levels in RA patients. We then calculated the haplotype frequencies defined by these SNPs for both groups. The genotype and allele frequencies of the TSLP SNPs did not differ significantly between the RA patients and the healthy controls. We also found that TSLP SNPs in the RA patients had no significant association with the levels of RF or anti-CCP. Our results suggest that TSLP SNPs are not associated with susceptibility to RA.

Human IL-27p28 Gene Polymorphisms are Associated with the Serum Total IgE Levels of Allergic Rhinitis Patients

Interleukin 27 (IL-27) was discovered as a heterodimeric cytokine of the IL-12 family, and is composed of two subunits - Epstein-Barr virus induced gene 3 (EBI3) and p28. It acts as a versatile cytokine in the early regulation of Th1 initiation and in the negative regulation of the Th2 factor GATA binding protein 3 (GATA-3). This cytokine is mediated by the IL-27 receptor (WSX-1), which is highly expressed on CD4? T lymphocytes and NK cells. We previously identified four polymorphisms in the human IL-27p28 gene and suggested that the polymorphism of IL-27p28 is associated with susceptibility to asthma. To determine whether these IL-27p28 SNPs are associated with susceptibility to allergic rhinitis, the genotype and allele frequencies of IL-27p28 SNPs were analyzed between allergic rhinitis patients and healthy controls. Although the genotype and allele frequencies of IL-27p28 SNPs in allergic rhinitis patients were not significantly different from those of the control group, there was a suggestive difference (P=0.037) between these groups in total serum IgE levels in the g.2905T＞G SNP of the IL-27p28 gene. Our result implies that the g.2905T＞G SNP of the IL-27p28 gene might have an affect on IgE production in allergic rhinitis patients.