Tzu-Yang Chang

Genetic Variation in the Vascular Endothelial Growth Factor Gene is Associated With Biliary Atresia

Background and Goals: Biliary atresia (BA) is a chronic inflammatory disease of the bile ducts resulting in biliary cirrhosis. Vascular endothelial growth factor (VEGF) has been implicated in cell-mediated inflammatory reactions. We aimed to study the relationship between genetic variations of the VEGF gene and susceptibility to BA using both case-control and family-based methodologies. Study: A total of 45 Taiwanese children with BA, 160 ethnically matched healthy controls, and 40 families (consisting of parents, affected children, and unaffected siblings) were studied. Three functional VEGF polymorphisms (−2578 A/C, −634 G/C, and +936 C/T) were assessed by using TaqMan assay. Results: The +936 CC genotype [odds ratio (OR) 3.51, 95% confidence interval 1.54-8.01, Pc=0.006] and C allele (OR 3.19, 95% confidence interval 1.48-6.90, Pc=0.004) were significantly associated with increased risk of BA. The association of the +936 C allele with BA was also confirmed in a family-based association study (OR 5.7, χ2=9.8, Pc=0.005). None of the haplotypes studied significantly influenced the risk to BA in either the case-control or family data sets. Conclusions: The VEGF +936 C/T polymorphism and particularly the C allele are associated with BA, possibly conferring increased susceptibility to the disease.

Prenatal diagnosis of choledochal cyst using ultrasound and magnetic resonance imaging

A 25-year-old primigravid woman was referred at 30 weeks’ gestation to evaluate a fetal intra-abdominal cystic mass. Sonographic examinations revealed a singleton fetus with biometry consistent with 30 weeks of gestation. An intra-abdominal cystic mass measuring 22 × 12 mm was noted. The amniotic fluid volume was normal. Color Doppler ultrasound revealed no flow within the mass. The cyst connected via the cystic duct to the gallbladder, raising the suspicion of a choledochal cyst (Figure 1). Ultrafast magnetic resonance imaging (MRI) scans further depicted a detailed anatomical relationship of the choledochal cyst to the liver, gallbladder and biliary tract (Figure 2). The choledochal cyst consisted of a cystic dilation of the common bile duct without dilation of the gallbladder and intrahepatic bile ducts. A diagnosis of Type IA choledochal cyst was thus made. The size of the cyst remained unchanged during follow-up ultrasound examinations. At 39 weeks’ gestation a female infant was born by vaginal delivery with Apgar scores of 10 and 10 at 1

Prenatal diagnosis of otocephaly with microphthalmia/anophthalmia using ultrasound and magnetic resonance imaging

A 30-year-old primigravid woman was referred to hospital at 29 weeks’ gestation because of polyhydramnios and regular uterine contractions. She and her husband were non-consanguineous and healthy. There was no family history of congenital malformations, nor any history of teratogenic medication, recent infection, diabetes mellitus, or hypertension during this pregnancy. A level II, twodimensional (2D) ultrasound examination revealed a single live fetus with a biparietal diameter of 7.99 cm (appropriate for 29 weeks’ gestation), a femur length of 5.4 cm (29 weeks), an abdominal circumference of 24 cm (29 weeks), polyhydramnios with an amniotic fluid index of 45 cm, absence of the mandible, hypotelorism, lowset ventromedially displaced ears, left microphthalmia with an ocular diameter of 1.29 cm (< 5th centile), and right anophthalmia with absence of the right lens (Figure 1). A tentative diagnosis of otocephaly was made. Magnetic resonance imaging (MRI) demonstrated agnathia and right anophthalmia (Figure 2). The other internal organs were unremarkable. A 1404-g female baby (Figure 3) was delivered 1 day later because of premature rupture of the membranes and preterm labor. The proband died shortly after birth. Autopsy confirmed the diagnosis of otocephaly, which was characterized by the isolated agnathia, aglossia, microstomia, and synotia without central nervous system and other organ defects except for the ocular abnormalities of left microphthalmia and absence of the right lens. The karyotype of the proband was 46,XX. Computed tomography (CT) scans following three-dimensional (3D) reconstruction showed a characteristic otocephalic skull (Figure 4). Prenatal diagnosis of otocephaly using 2D and 3D ultrasound has been well described in the literature1–5. To the best of our knowledge, this

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 Polymorphisms in the CD40 Ligand Gene and Kawasaki Disease

BackgroundAlthough some previous studies have reported that genetic and immunological factors play important roles in the pathogenesis of Kawasaki disease (KD), the etiological factors of this enigmatical pediatric disease are still poorly understood.PurposeThis study aims to investigate whether polymorphisms of the CD40 ligand (CD40L) gene are associated with KD and the development of coronary artery lesions (CAL) in the Taiwanese children.Materials and methodsThe CD40L −3459 A/G and IVS4+121 A/G single nucleotide polymorphisms (SNPs) were genotyped in 167 children with KD and 1,010 ethnically matched healthy controls by TaqMan assay.ResultsNone of the CD40L polymorphisms was associated with susceptibility or CAL development of KD, and this finding was supported by the haplotype analysis.ConclusionIn summary, these results provide little support for specific CD40L SNPs in the susceptibility or CAL development of KD in Taiwanese children. However, it will be necessary to validate or replicate this association in other independent large-size ethnic groups.

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 -590 C/T and 8375 A/G interleukin-4 polymorphisms are not associated with Kawasaki disease in Taiwanese children.

Although some previous studies have reported that genetic and immunologic factors play important roles in the pathogenesis of Kawasaki disease (KD), the etiologic factors of this enigmatical pediatric disease are still poorly understood. This study aims to investigate whether polymorphisms of the interleukin-4 gene (IL-4; -590 C/T in the promoter region and 8375 A/G in intron 3) are associated with KD and the development of coronary artery lesions (CALs) in Taiwanese children. Genomic DNA was extracted from whole-blood samples from 150 children with KD and 472 ethnically matched healthy control subjects. The IL-4 -590 C/T and 8375 A/G single nucleotide polymorphisms (SNPs) were genotyped by a real-time polymerase chain reaction system with the Pre-Developed TaqMan Allelic Discrimination Assay. No significant associations between IL-4 SNPs and susceptibility of KD with CALs were found. In addition, no evidence for associations between IL-4 SNPs and CAL development was found. These results suggest that IL-4 -590 C/T and 8375 A/G SNPs do not confer a relevant role in the susceptibility or CAL development of KD in Taiwanese children.

Lack of association of the vascular endothelial growth factor gene polymorphisms with Kawasaki disease in Taiwanese children.

IntroductionKawasaki disease (KD) is an acute febrile vasculitis of unknown etiology that mainly occurs in infants and children. Clinical and histopathologic findings suggest that vascular endothelial growth factor (VEGF) is involved in the coronary artery lesions (CALs) development in KD. This study hypothesized that specific VEGF gene polymorphisms and their haplotypes are associated with KD susceptibility and CAL development in Taiwanese children.Subjects and MethodsThe VEGF −2578 A/C, −634 G/C, and +936 C/T single-nucleotide polymorphisms (SNPs) were genotyped in 156 children with KD and 672 ethnically matched healthy controls using the Pre-Developed TaqMan Allelic Discrimination Assay.ResultsNo significant differences in genotype, allele, carrier, and haplotype frequencies of the three SNPs were found between healthy controls and children with KD or between patients with and without CAL.ConclusionOur data suggest that VEGF −2578 A/C, −634 G/C, and +936 C/T SNPs do not confer increased susceptibility to KD or to CAL development.

Association of polymorphisms in the Interleukin-18 gene with susceptibility to biliary atresia.

Background and Objective:Biliary atresia (BA) is a destructive inflammatory obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. Although the etiology is unknown, immunologically mediated injury of the bile ducts triggered by as yet unidentified infectious agents is likely to play a critical role. Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of its induction of interferon-gamma. In this study, we investigated whether polymorphisms of the IL18 gene were associated with susceptibility to BA. Patients and Methods:Genomic DNA was extracted from whole-blood samples of 50 Taiwanese children with BA and 1117 ethnically matched healthy controls. The IL18 –1297 T/C, –607 C/A, –137 G/C, and +105 A/C polymorphisms were genotyped using the TaqMan assay. Results:No statistically significant differences of genotype, allele, carrier, and haplotype frequencies of these IL18 gene variants were found between children with BA and healthy controls. Conclusions:Our data suggest that the IL18 gene does not play a major role in BA predisposition in Taiwanese children.