Wen-Shan Lin

Association of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study.

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21–1.84; corrected P value [Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15–1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27–2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22–2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D’ = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population.

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.

The IL18 gene and Hashimoto thyroiditis in children

Interleukin 18 (IL18) stimulates interferon-γ production in Th1 cells which are prominent in the thyroid of Hashimoto thyroiditis (HT). We investigated the association between the IL18 gene and HT. There were 116 children with HT and 1272 controls. rs187238 and rs1946518 in the promoter region of the IL18 gene were genotyped. Differences in genotype, allele, carrier, and haplotype distributions between patients and controls were compared. A Pc value <0.05 was considered significant. The frequency of the C/G genotype of rs187238 was significantly higher in patients and conferred a risk of HT (OR, 1.96; 95% CI, 1.30-2.95; Pc, 0.0021). So did the frequencies of allele C (OR, 1.73; 95% CI, 1.22-2.44; Pc, 0.0035) and carrier C (OR, 1.96; 95% CI, 1.31-2.92; Pc, 0.0017), however the frequency of the G/G genotype was significantly lower in patients than in controls (OR, 0.51; 95% CI, 0.34-0.76; Pc, 0.0034). There was no association between HT and rs1946518. The CT haplotype was significantly more frequent in patients than in controls and conferred a risk of HT (OR, 1.76; 95% CI, 1.24-2.49; Pc, 0.0049). We concluded that the IL18 gene was associated with HT in children. The rs187238C allele and CT haplotype conferred a risk of HT.

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.

Replication of results from a cervical cancer genome-wide association study in Taiwanese women

Genetic epidemiological studies show that genetic factors contribute significantly to cervical cancer carcinogenesis. Several genome-wide association studies (GWAS) have revealed novel genetic variants associated with cervical cancer susceptibility. We aim to replicate 4 GWAS-identified single nucleotide polymorphisms (SNPs), which were associated with invasive cervical cancer in Chinese women, in a Taiwanese population. The rs13117307 C/T, rs8067378 A/G, rs4282438 G/T, and rs9277952 A/G SNPs were genotyped in 507 women with cervical squamous cell carcinoma (CSCC) and 432 age/sex matched healthy controls by using TaqMan PCR Assay. Human papillomavirus (HPV) DNA test and typing were performed in CSCC patients. Only the rs4282438 SNP was found to be significantly associated (G allele, odds ratio [OR] = 0.67, P = 1.5 × 10−5). This protective association remained in HPV-16 positive CSCC subgroup (G allele, OR = 0.60, P = 1.2 × 10−5). In conclusion, our study confirms the association of rs4282438 SNP with CSCC in a Taiwanese population. However, larger sample sets of other ethnic groups are required to confirm these findings.

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.