Shih-Chuan Chang

Association of CTLA4 gene A-G polymorphism with rheumatoid arthritis in Chinese.

The aim of this study was to investigate the allelic association of a single nucleotide polymorphism in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene with rheumatoid arthritis (RA) in Chinese people. One hundred and eighty-six unrelated adults with RA and 203 randomly selected normal adults were studied. All were ethnic Chinese living in Taiwan. The CTLA4 A-G polymorphism was genotyped with a polymerase chain reaction (PCR) and digestion with the restriction enzyme BstEII. The genotype and allele frequencies of CTLA4 in patients with rheumatoid arthritis differed significantly from those of adult controls (#E5/E5#=0.022 and #E5/E5#=0.037, respectively). Genotype CTLA4 49 G/G and allele G were associated with an increased risk of RA (RR=1.72, 95% CI=1.15–2.57, #E5/E5#=0.008; RR=1.39, 95% CI=1.02–1.89, #E5/E5#=0.037, respectively), whereas genotype A/G and allele A were associated with protection against RA (RR=0.58, 95% CI=0.39–0.87, #E5/E5#=0.008 and RR=0.72, 95% CI=0.53–0.98, #E5/E5#=0.037, respectively). We concluded that, the CTLA4 49 A-G polymorphism is associated with RA in Chinese patients from Taiwan.

Polymorphism of Transmembrane Region of MICA Gene and Kawasaki Disease

Kawasaki disease is a febrile disease of children complicated with vasculitis of the coronary arteries and potential aneurysm formation. It has been recognized worldwide and appears to be increasing in frequency. Studies have found that Kawasaki disease is associated with major histocompatibility complex (MHC) class I B antigens. The MHC-class-I-chain-related gene A (MICA) is located near HLA-B. It has a triplet repeat microsatellite polymorphism in the transmembrane region. We investigated the microsatellite polymorphism in children with Kawasaki disease and controls. Seventy children (46 boys), age at diagnosis 1.68 ± 1.69 years, with Kawasaki who were treated with aspirin as well as intravenous gamma-globulin were enrolled. Control subjects consisted of 154 children (87 boys), age 2.81 ± 2.12 years. Phenotype frequency of allele A4 in patients with aneurysm formation was significantly lower than in patients without aneurysms [relative risk (RR) = 0.06, 95% confidence interval (CI) = 0.01–0.48, p = 0.00469, pc = 0.0232] and showed a similar tendency when compared with controls. Gene frequency of allele A4 was also significantly lower in patients who developed aneurysms than in patients who did not (RR = 0.07, 95% CI = 0.01–0.57, p = 0.0057, pc = 0.0282). Gene frequency of allele A5 showed a tendency to be higher in patients who developed aneurysms than in controls (RR = 2.35, 95% CI = 0.98–5.63, p = 0.0486, pc = 0.220). Allele A5.1 tended to be negatively associated with Kawasaki disease (RR = 0.57, 95% CI = 0.35–0.93, p = 0.022, pc = 0.105). Our study showed that allele A4 was negatively associated with coronary aneurysm formation in Kawasaki disease. This suggests that allele A4 protects the children with Kawasaki disease from developing coronary aneurysms after aspirin and gamma globulin therapy.

Polymorphism in the transmembrane region of the MICA gene and type 1 diabetes.

Although MHC class II genes have a stronger association with type 1 diabetes than MHC class I genes, studies have shown that MHC class I molecules play an independent role in the etiology of type 1 diabetes, and the existence of susceptibility genes within a segment of MHC between the HLA-B and TNF genes has been predicted, where MHC class I chain-related gene A (MICA) resides. MICA has a triplet repeat polymorphism in the transmembrane region consisting of five alleles. We analyzed this polymorphism in 162 unrelated children (82 boys) with type 1 diabetes (age at diagnosis 7.01 +/- 3.76 yr) and 154 randomly selected unrelated children (87 boys), age 2.81 +/- 2.12 yr. Phenotype frequency of allele A9 in children with type 1 diabetes was significantly higher than in controls (RR = 2.42, 95% CI = 1.52-3.85, p = 0.000162, pc = 0.00081). Gene frequency of allele A9 was also significantly higher in children with type 1 diabetes when compared with control children (RR = 2.73, 95% CI = 1.85-4.03, p = 2.62 x 10(-7), pc = 1.31 x 10(-6)). This study demonstrates that MICA allele A9 confers risk of type 1 diabetes.

Human leucocyte antigen-G polymorphisms are associated with cervical squamous cell carcinoma risk in Taiwanese women

BACKGROUND The mere presence of human papillomavirus (HPV) is not enough for cervical cancer development and immunogenetic background may play an important role. Human leucocyte antigen (HLA)-G acts as a negative regulator of immune responses and its expression in tumour cells may enable them to avoid immune attack. We aim to study if polymorphisms in the HLA-G gene are associated with cervical cancer risk in Taiwanese women. METHODS +1537 A/C, 14-bp deletion/insertion (Del/Ins), and +3142 G/C polymorphisms were genotyped in a hospital-based study of 317 women with cervical squamous cell carcinoma (CSCC) and 400 healthy control women frequency matched by age. The presence and genotypes of HPV in CSCC were determined. RESULTS We found the +3142 C/C genotype and C allele were associated with increased risk for CSCC (adjusted odds ratio [OR]=1.78, P=0.004; adjusted OR=1.31, P=0.014, respectively). In subgroup analysis based on HPV type 16 positivity, significant associations with higher adjusted ORs were found in +3142 C/C genotype and C allele (adjusted OR=2.19, P=0.001; adjusted OR=1.48, P=0.003, respectively) and +1537 C/C genotype and C allele frequencies increased significantly (adjusted OR=2.88, P=0.004; adjusted OR=1.69, P=0.0005, respectively). Furthermore, the C-Del-C haplotype conferred increased risk of both CSCC and HPV-16 positive CSCC women (adjusted OR=1.41, P=0.009; adjusted OR=1.94, P=0.0001, respectively). CONCLUSION These findings suggest that HLA-G gene is involved in the susceptibility to CSCC.

Genetic variants in interleukin-18 gene and risk for cervical squamous cell carcinoma.

Cervical cancer is strongly associated with infection of oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for progression to cervical cancer. It is now recognized that host immunogenetic background participates in the control of HPV infection and development of cervical cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays a central role in antitumor immunity. The aim of this study is to determine if potentially functional polymorphisms in IL-18 gene are associated with risk of HPV-induced cervical cancer in Taiwanese women. Pre-Developed TaqMan Allelic Discrimination Assay was used to genotype IL-18 -1297 T/C, -607 C/A, -380 C/G, -137 G/C, and +105 A/C polymorphisms in a hospital-based study of 470 women with cervical squamous cell carcinoma (CSCC) and 722 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined by PCR. None of the polymorphisms or any haplotype was found to have significant differences in distribution among all subjects with CSCC, those with HPV-16 positive CSCC, and controls. Our results suggest that the IL-18 -1297 T/C, -607 C/A, -380 C/G, -137 G/C, and +105 A/C polymorphisms are not associated with susceptibility to CSCC in Taiwanese women.

The HLA-B gene and Hashimoto disease in Han Chinese children: a case-control and family-based study.

Hashimoto disease (HD) is an autoimmune thyroid disease resulting from complex interactions between genetic and environmental factors. The human leukocyte antigen (HLA) gene has been established to be involved in the susceptibility to HD. We aim to investigate the associations between HLA-B alleles and Han Chinese children with HD by both case-control and family-based studies. A total of 108 unrelated children with HD, 380 unrelated healthy controls, 58 trios of affected patients and their parents, and 75 trios of unaffected siblings and their parents were recruited. HLA-B genotyping was performed by polymerase chain reaction and detected with a sequence-specific oligonucleotide probes system. We found that B*46:01 allele (OR = 2.31, 95% CI 1.60-3.34, P(c) = 9.99 × 10(-5)) and carrier (OR = 3.28, 95% CI 2.10-5.11, P(c) = 1.35 × 10(-6)) were associated with HD risk. Transmission/disequilibrium test further confirmed an overtransmission of the B*46:01 (OR 2.55, 95% CI 1.36-6.10, P = 6.5 × 10(-3)). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-B*46:01 confers susceptibility to HD in Han Chinese children. Further studies with larger children cohort are required to confirm the role of B*46:01 in the development of HD.

ITPR3 gene haplotype is associated with cervical squamous cell carcinoma risk in Taiwanese women

Host immunogenetic background plays an important role in human papillomavirus (HPV) infection and cervical cancer development. Inositol 1,4,5-triphosphate receptor type 3 (ITPR3) is essential for both immune activation and cancer pathogenesis. We aim to investigate if ITPR3 genetic polymorphisms are associated with the risk of cervical cancer in Taiwanese women. ITPR3 rs3748079 A/G and rs2229634 C/T polymorphisms were genotyped in a hospital-based study of 462 women with cervical squamous cell carcinoma (CSCC) and 921 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. No significant association of individual ITPR3 variants were found among controls, CSCC, and HPV-16 positive CSCC. However, we found a significant association of haplotype AT between CSCC and controls (OR = 2.28, 95% CI 1.31–3.97, P = 2.83 × 10−3) and the OR increased further in CSCC patients infected with HPV-16 (OR = 2.89, 95% CI 1.55–5.37, P = 4.54 × 10−4). The linkage disequilibrium analysis demonstrated that ITPR3 association with CSCC was independent of HLA-DRB1 alleles. In conclusion, these findings suggest that AT haplotype in the ITPR3 gene may serve as a potential marker for genetic susceptibility to CSCC.

Investigation of cytotoxic T-lymphocyte-associated protein 4 gene polymorphisms in symptomatic gallstone disease

Gallstone disease (GSD), which is increasingly prevalent in Taiwan, develops through a complex process involving genetic, environmental, and immune factors. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) limits T-cell proliferation. The present study looked for associations between symptomatic GSD and polymorphisms of the CTLA4 gene. For this case-control cross-sectional study among Taiwanese, 275 patients with symptomatic GSD and 852 controls were enrolled. Genotyping of CTLA4-318 C/T, +49 A/G, and CT60 A/G single nucleotide polymorphisms (SNPs) was performed by polymerase chain reaction-restriction fragment length polymorphism. The genotype, allele, carrier, and haplotype frequencies were calculated by direct counting or with Haploview 4.1 software. Genotype, allele, carrier, and haplotype frequencies of the CTLA4 SNPs studied were equally distributed in symptomatic GSD patients and controls. No significant associations between symptomatic GSD and these 3 SNPs were observed. Our data suggest that CTLA4-318 C/T, +49 A/G, and CT60 A/G SNPs do not confer increased susceptibility to symptomatic GSD.

Functional variant of the P2X7 receptor gene is associated with human papillomavirus-16 positive cervical squamous cell carcinoma

Human papillomavirus (HPV) infection and the fate of HPV infected cervical epithelial cells are strictly associated with cervical cancer development. P2X7 receptor has been implicated in both the regulation of immune responses and apoptosis of cervical cancer cells. The study aims to investigate if polymorphisms in the P2RX7 gene are associated with the risk of cervical cancer in Taiwanese women. P2RX7 253 T/C, 835 G/A, and 1513 A/C loss-of-function polymorphisms were genotyped in a hospital-based study of 507 women with cervical squamous cell carcinoma (CSCC) and 1619 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. The frequency of 253 C/C genotype was found to increase significantly in patients with HPV-16 positive CSCC compared with controls (odds ratio = 10.2, 95% confidence interval 1.39–87.8, Pc = 0.03). No significant associations were found for other 2 polymorphisms. Analysis of haplotypes also revealed no significant differences among women with CSCC, those with HPV-16 positive CSCC and controls. In conclusion, inheritance of the C/C genotype at position 253 in the P2RX7 gene may contribute to the risk of HPV-16 associated CSCC in Taiwanese women.

Gender-specific association of the interleukin 18 gene with symptomatic gallstone disease.

Symptomatic gallstone disease (SGSD) induced several inflammatory responses and affected extrahepatic bile ducts. Although the pathology and environmental risk factors of gallstone disease are well documented, immune or inflammatory responses in SGSD development are still inconclusive. Interleukin 18 (IL18) is a pro‐inflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of the induction of interferon‐γ. In this study, we investigated whether polymorphisms of the IL18 gene were associated with SGSD susceptibility.