Genetic susceptibility to cervical squamous cell carcinoma is associated with HLA-DPB1 polymorphisms in Taiwanese women.

Cervical cancer is a multifactorial disease, and increasing evidence suggests that host immunogenetic background may contribute to its pathogenesis. Genetic variations in human leukocyte antigen (HLA) genes may alter the efficiency of immune response to human papillomavirus (HPV) antigens and have been implicated in the risk of cervical cancer. We investigated whether polymorphisms in the HLA-DPB1 gene were associated with cervical cancer risk in a Taiwanese population. HLA-DPB1 alleles and +550 G/A polymorphism were genotyped in a case-control study of 473 women with cervical squamous cell carcinoma (CSCC) and 676 healthy controls. The presence and genotypes of HPV in CSCC were determined. We found that the DPB1*05:01 and +550 A alleles were associated with decreased and increased risk of CSCC, respectively [odds ratio (OR) = 0.72, Pc = 0.001; OR = 1.25, Pc = 0.03]. In subgroup analysis based on HPV type 16 positivity, significant associations were shown in the DPB1*05:01 and *13:01 alleles (OR = 0.65, Pc = 0.0007; OR = 1.83, Pc = 0.004). Furthermore, the DPB1*05:01-G and *13:01-G haplotypes conferred decreased and increased risk of both CSCC and HPV-16 positive CSCC women, respectively (OR = 0.72, Pc = 0.0009; OR = 0.63, Pc = 0.0004 for DPB1*05:01-G; OR = 1.55, Pc = 0.03; OR = 1.84, Pc = 0.004 for DPB1*13:01-G). A risk haplotype DPB1*02:01-A was also observed in the HPV-16 positive CSCC women (OR = 1.51, Pc = 0.05). These findings suggest that HLA-DPB1 gene is involved in the CSCC development.

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

BACKGROUND AND AIM: 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. METHODS: Genomic DNA was isolated from the whole blood samples of 445 patients with SGSD and 1121 gallstone-free controls. The IL18 rs549908T>G, rs5744247C>G, rs187238G>C, rs1946518T>G, and rs360719A>G polymorphisms were genotyped using predeveloped TaqMan allelic discrimination assay. RESULTS: We found IL18 rs5744247G allele conferred protection against SGSD in female patients (odds ratio = 0.75, corrected P-value = 0.015). Haplotype analysis revealed that TGGTA protected females from SGSD development (odds ratio = 0.75, corrected P-value = 0.02). CONCLUSIONS: Based on our findings, IL18 rs5744247C>G polymorphism could be a potential genetic marker to predict SGSD susceptibility in Han Chinese women.

Genetic polymorphisms in the ITPKC gene and cervical squamous cell carcinoma risk.

Cervical cancer is caused primarily by infection with oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for the progression to cervical cancer. Host immunogenetic factors may involve in the development of this disease. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is recently shown to act as a negative regulator of T-cell activation. We aim to study if polymorphisms in the ITPKC gene are associated with the risk of cervical cancer in Taiwanese women. ITPKC rs28493229 C/G, rs890934 G/T, rs2303723 C/T, and rs10420685 A/G polymorphisms were genotyped in a hospital-based study of 465 women with cervical squamous cell carcinoma (CSCC) and 800 age-matched healthy control women. The presence and genotypes of HPV in CSCC were determined. The frequency of G/G genotype and G allele of the ITPKC rs28493229 polymorphism was significantly higher in patients with CSCC compared with controls (OR = 1.81, 95 % CI 1.20-2.73, P = 0.005, P (c) = 0.02; OR = 1.70, 95 % CI 1.14-2.54, P = 0.008, P (c) = 0.03, respectively). No significant associations were found for other 3 polymorphisms. Haplotype analysis revealed the distribution of haplotype CGTA was significantly reduced in women with CSCC (OR = 0.59, 95 % CI 0.40-0.89, P = 0.01, P (c) = 0.04). In conclusion, we found the G/G genotype and G allele of the ITPKC rs28493229 polymorphism may contribute to the risk of CSCC in Taiwanese women. This finding provides new insights into the mechanisms of immune activation in cervical cancer.

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.

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.

Polymorphism in the transmembrane region of the major histocompatibility complex class I chain-related gene A: association of five GCT repetitions with Graves' disease in children.

Graves' disease is an autoimmune disease involving a complex interplay of multiple genetic and environmental influences. An association between the disorder and the major histocompatibility complex (MHC; human leukocyte antigen [HLA]) region has long been reported. The major histocompatibility complex class I chain-related gene A (MICA) has a triplet repeat polymorphism in the transmembrane region consisting of six alleles. For this study, the polymorphism in question was analyzed for 129 unrelated children with Graves' disease (97 girls and 32 boys, 10.0 +/- 3.0 years of age) and 396 randomly selected, unrelated subjects (205 females, 191 males, 8.4 +/- 13.5 years of age). The frequencies of genotype A5/A5 and A5/A5.1 were significantly higher in patients than in controls (relative risk [RR] = 2.49, 95% confidence interval [CI] 1.52-4.10, p = 0.00024, pc = 0.0035 and RR = 2.13, 95% CI 1.31-3.47, p = 0.0020, pc = 0.030; respectively). The frequency of genotype A5.1/A5.1 was significantly lower in patients than in controls (RR = 0.09, 95% CI 0.01-0.66, p = 0.0030, pc = 0.044). Allele frequency for allele A5 was significantly higher for children with Graves' disease compared to controls (RR = 2.12; 95% CI = 1.59-2.82; p = 1.9 x 10(-7); pc = 9.5 x 10(-7)). This study demonstrates that MICA allele A5 confers the risk for Graves' disease.

Polymorphism in transmembrane region of MICA gene and cholelithiasis.

AIM: To study the significance of polymorphism of MHC class I chain-related gene A (MICA) gene in patients with cholelithiasis. METHODS: Subjects included 170 unrelated adults (83 males) with cholelithiasis and 245 randomly selected unrelated adults (130 males) as controls. DNA was extracted from peripheral leukocytes and analyzed for polymorphism of 5 alleles (A4, A5, A5.1, A6 and A9) of the MICA gene. RESULTS: There was no significant difference in phenotype, allele, and genotype frequencies of any of the 5 alleles between cholelithiasis patients and controls. CONCLUSION: This study demonstrates that MICA alleles studied bear no relation to cholelithiasis.

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.

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.

Influence of HLA-DRB1 genes and the shared epitope on genetic susceptibility to rheumatoid arthritis in Taiwanese.

OBJECTIVE: To investigate the association of predisposing and protective HLA-DRB1 alleles with rheumatoid arthritis (RA) and its clinical markers in a Taiwanese population. METHODS: A total of 273 patients with RA and 480 healthy controls, all of Taiwanese origin, were genotyped for HLA-DRB1 alleles by polymerase chain reaction and sequence-based typing assays. The associations between RA and HLA-DRB1 alleles and genotypes were investigated by chi-squared test. RESULTS: The DRB1*0405 and *1001 phenotypes showed the most significant associations with RA (OR 4.04, 95% CI 2.84-5.77, pc = 3.2 10(-14); OR 5.25, 95% CI 2.10-13.06, pc = 3.0 10(-3), respectively). Individuals carrying single or double doses of the shared epitope (SE/non-SE or SE/SE) had higher risks of RA. The compound heterozygote of DRB1*0405/*1001 showed the largest increase in RA risk (OR 15.8, 95% CI 2.48-100.7, pc = 0.004). Single or double doses of SE alleles were significantly associated with a higher bone erosion rate. Rheumatoid factor positivity and bone erosion were more frequent in patients with at least one copy of DRB1*0405. CONCLUSION: Our results show that SE-encoding HLA-DRB1*0405 and *1001 are associated with RA in a Taiwanese population; this is the first time DRB1*1001 has been described in persons of Asian ethnicity. Heterozygotes of DRB1*0405 and *1001 predicted the strongest susceptibility to RA, suggesting that this genotype enhances susceptibility to RA in Taiwanese.