Marie Lin

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.

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.

Molecular analysis of HLA-DRB1 allelic associations with systemic lupus erythematous and lupus nephritis in Taiwan

To evaluate the association of human leukocyte antigen (HLA)–DRB1 alleles with systemic lupus erythematosus (SLE) and lupus nephritis (LN) in the Taiwanese population, and to investigate the possible association of HLA-DRB1 alleles with disease severity in LN. HLA-DRB1 alleles were studied in 105 SLE patients (82 patients with LN, 23 patients without LN) and 855 healthy controls by polymerase chain reaction and sequence-based typing assays. The frequency of the HLA class II alleles DRB1*0301 (Odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.31–3.10, Pc = 0.02) and DRB1*1501 (OR = 2.06, 95% CI = 1.36–3.13, Pc = 0.01) were both increased in SLE patients, compared to healthy controls. The frequency of DRB1*1202 was significantly lower in LN patients than in SLE patients without nephritis (OR = 0.23, 95% CI = 0.09–0.57, Pc = 0.01). No specific allele was significantly associated with an increased or decreased risk for severity of LN in this sample. In Taiwanese people, the DRB1*0301 and DRB1*1501 alleles are significant risk factors for SLE, while the DRB1*1202 allele is protective for LN.

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.

Association of an IL-4 gene haplotype with Graves disease in children: experimental study and meta-analysis

Investigations of an association between Graves disease (GD) and the IL-4 gene have yielded conflicting results. We performed a case-control study of IL-4 gene polymorphisms possibly associated with GD, as well as a meta-analysis of other such studies. We genotyped IL-4 single nucleotide polymorphisms (SNPs) rs2243250 and rs2243289 in 220 unrelated children with GD and 904 healthy controls. No significant differences between patients and controls were observed in the genotype, allele, or carrier frequencies of the 2 SNPs. The levels of autoantibodies did not differ significantly between the genotypes of each SNP. Linkage disequilibrium between the 2 SNPs was strong in the controls (D, 0.916; r(2), 0.824). Haplotype TA conferred a significant risk of GD (odds ratio = 2.47, 95% confidence interval 1.24-4.95, corrected p value = 0.033). The T allele frequency of rs2243250 was 80.0% in Asians, significantly higher than the 12.6% in Caucasians (p = 1.4 × 10(-269)). Meta-analysis of data from 8 published reports and our own study did not reveal any significant association between these SNPs and GD. Our study showed an association between the IL-4 gene and GD in children, but only using a haplotype-based method, suggesting that this might be a better approach than evaluating individual SNPs.

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.

Association of Interferon-Gamma Gene Polymorphisms in Taiwanese Children with Biliary Atresia

BackgroundBiliary atresia (BA) is a devastating neonatal hepatobiliary disease characterized by bile duct inflammation and fibrosis. The pathogenesis remains unclear, but immunologically mediated injury to bile ducts following an infectious insult is likely to play a critical role. Interferon-gamma (IFN-γ) is a key cytokine that affects immune-mediated inflammatory responses.ObjectiveThis study aims to investigate whether polymorphisms of the IFN-γ (IFNG) gene were associated with susceptibility to BA.MethodsThe IFNG −1615 C/T, −183 G/T, +874 A/T, and +2197 A/G polymorphisms were genotyped using the TaqMan assay, and CA repeat microsatellite was analyzed using capillary electrophoresis in 50 children with BA and 788 ethnically matched healthy controls.ResultsThe distribution of genotype, allele, and haplotype frequencies of these IFNG gene variants did not differ significantly between children with BA and controls.ConclusionPolymorphisms of the IFNG gene do not appear to play a major role in the genetic predisposition to BA in Taiwanese children.

Association of CT60 Polymorphism of the CTLA4 Gene with Graves' Disease in Taiwanese Children

BACKGROUNDnThe CTLA4 gene is involved in the activity of T cells.nnnAIMnTo determine the association between Graves disease (GD) susceptibility and CT60 polymorphism of the CTLA4 gene.nnnPATIENTSn189 children with GD and 620 healthy controls.nnnMETHODSnWe determined the genotype with restriction fragment length polymorphism and compared results.nnnRESULTSnGenotype G/G was significantly associated with GD (odds ratio [OR] = 1.71, 95% confidence interval [CI] 1.20-2.44, Pc = 0.006); however, allele A could reverse its effect. Allele G was significantly more frequent (OR = 1.61, 95% CI 1.18-2.19, Pc = 0.0049) but allele A (OR = 0.62, 95% CI 0.46-0.85, Pc = 0.0049) and phenotype A (OR = 0.58, 95% CI 0.41-0.83, Pc = 0.006) were less frequent in patients with GD than in controls.nnnCONCLUSIONnThe CT60 SNP was associated with susceptibility to GD. The G allele increased the risk of GD.

Genetic variability of interleukin4 gene in Taiwanese children with biliary atresia.

Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology that leads to biliary cirrhosis and is the most common cause of liver transplantation in children. A still undetermined hepatobiliary viral infection may elicit an uncontrollable autoimmune response against the biliary epithelial cells in genetically predisposed children and culminates in atresia of the biliary trees. Interleukin 4 (IL4) is crucial for the differentiation of naive T helper cells into the T helper 2 effector cells that promote humoral immunity. This study aims to investigate whether polymorphisms of the IL4 gene are associated with susceptibility to BA. Genomic DNA was extracted from whole blood samples of 53 Taiwanese children with BA and 904 ethnically-matched healthy controls. The IL4 -590 C/T, -33 C/T, and 8375 A/G polymorphisms were genotyped using the Pre-Developed TaqMan Allelic Discrimination Assay in a real-time polymerase chain reaction system. No significant difference between children with BA and healthy controls were found when comparing genotype, allele, carrier, and haplotype frequencies of these IL4 gene variants. These results suggest that the tested polymorphisms of IL4 gene are unlikely to contribute significantly to BA susceptibility in Taiwanese children.