Genetic variations of HLA-DRB1 and susceptibility to 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 enigmatic pediatric disease are still poorly understood. The purpose of this study was to investigate whether polymorphisms of the human leukocyte antigen DRB1 (HLA-DRB1) gene are associated with KD and the development of coronary artery lesions (CAL) in Taiwanese children. Genomic DNA was extracted from whole blood samples from 145 children with KD and 331 healthy controls. The HLA-DRB1 gene was genotyped by polymerase chain reaction (PCR) and sequence-based typing assays. We found that the distribution of HLA-DRB1 allele families and alleles in children with KD did not differ from that in healthy controls. Stratified analysis did not demonstrate any association between particular HLA-DRB1 allele families or alleles and the development of CAL in children with KD. These findings suggest that susceptibility to KD and CAL is not associated with the HLA-DRB1 gene in a Taiwanese population. If immunogenetic determinants are involved in this disease and its complications in Taiwanese children, they must involve genes other than HLA-DRB1.

HLA-DRB1 alleles and cervical squamous cell carcinoma: experimental study and meta-analysis.

Polymorphisms in human leukocyte antigen (HLA) genes have been implicated in the risk for cervical cancer. Association of certain class II HLA alleles with cervical cancer has been documented in various ethnic populations. The implications of such an association, however, are controversial. We analyzed 126 Chinese women with cervical squamous cell carcinoma (CSCC) and 289 healthy controls to test associations of certain HLA-DRB1 alleles. We then performed meta-analyses combining our own experimental data and data from nine other published studies. We found no significant differences in HLA-DRB1 allele frequencies in both CSCC and HPV-16-positive CSCC patients and control subjects. Meta-analysis provided evidence that four allele families (HLA-DRB1*04, *07, *11, and *15) and seven alleles (HLA-DRB1*0403, *0405, *0407, *0701, *1501, *1502, and *1503) were positively associated and two allele families (HLA-DRB1*09 and *13) and four alleles (HLA-DRB1*0901, *1301, *1302, and *1602) were negatively associated with CSCC in all studies or in Caucasian subgroups. In conclusion, our meta-analysis confirms the apparent association between certain HLA-DRB1 allele families and alleles and CSCC, suggesting that oncogenesis in this disease may be related to defects in immunoregulation. Larger studies may be needed, particularly in various ethnic groups, to further substantiate these associations.

The CBLB gene and Graves' disease in children.

The CBLB gene functions as a negative regulator of autoimmunity. Impairment of the Cbl-b signaling pathway may contribute to human autoimmune disease. dbSNP rs2305035 is a C/T polymorphism located in exon 10 of the CBLB gene. We report an association study of this polymorphism in children with Graves' disease. The patients were 158 unrelated children (125 girls) with Graves' disease, aged 9.8 +/- 3.3 years. The controls consisted of 237 adults without a history of autoimmune disease. The C allele and phenotype frequencies of patients and controls were 247 (78.2%) vs 356 (75.1%) (OR = 1.19, p >0.05) and 151 (95.6%) vs 221 (93.2%) (OR = 1.56, p >0.05), respectively. The allelic polymorphism in patients and controls with and without DRB1*09012 were also not significantly different. This study demonstrates that the C/T polymorphism in exon 10 of the CBLB gene is not associated with Graves' disease in children.

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.

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.

Association of GST genotypes with age of onset and lymph node metastasis in oral squamous cell carcinoma.

BACKGROUND: Environment-gene interaction in oral carcinogenesis is well demonstrated by phase I and II enzymes that are involved in the metabolism of carcinogens. This study investigated the association of glutathione S-transferase (GST)T1 and GSTM1 genotypes of phase II enzyme genes with risk for, age of onset, and neck lymph node metastasis (LNM) in areca-associated oral squamous cell carcinoma (OSCC). METHODS: A total of 114 OSCC male patients and 100 male controls were recruited. All subjects were areca users and tobacco smokers. DNA was obtained from peripheral blood samples. Genotyping of GSTT1 (non-null/null) and GSTM1 (non-null/null) was determined by polymerase chain reaction (PCR) analysis using specific primers that only amplify non-null alleles. RESULTS: No association was found between GST genotype and the risk of OSCC based on case-controls. Patients with the GSTT1 null genotype were older at onset (P = 0.03). Those with the GSTM1 null genotype had a higher incidence of neck LNM than those with the GSTM1 non-null genotype (P = 0.01). Patients with the GSTM1/GSTT1 null genotype appeared to have later onset and a higher incidence of neck LNM than those carrying the opposite genotype. CONCLUSION: The GST genotypes may be important markers for the age of onset and risk of metastasis in OSCC. The data also suggest that the various GST isoforms may be differentially involved in development or progression of OSCC.

Polymorphism of the MICA gene and risk for oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF), an insidious, pre-cancerous, chronic disease that may affect the entire oral cavity and sometimes extend to the pharynx has been reported to be associated with immune function. The major histocompatibility complex (MHC) class I chain-related gene A (MICA) is expressed by keratinocytes and other epithelial cells, and its encoded protein interacts with gamma/delta T-cells localized in the submucosa. The MICA gene has a triplet repeat (GCT) polymorphism in the transmembrane domain resulting in five distinct allelic patterns. METHODS: We analyzed MICA polymorphism in 80 OSF patients and 351 randomly selected unrelated controls by using the ABI Prism 377-18 DNA sequencer (Applied Biosystems) to analyze the sample DNA PCR products. The number of microsatellite repeats was estimated with Genescan 672 software (Applied Biosystems) with a standard size marker of GS-350 TAMRA. RESULTS: The phenotype frequency of allele A6 of MICA in subjects with OSF was significantly higher than that in controls (OR = 3.48; 95% CI = 1.8-6.71; P = 0.0002), as was the frequency of the allele (OR = 2.65; 95% CI = 1.44-4.86; P = 0.001). CONCLUSION: The results suggest that allele A6 in MICA might confer a risk for OSF.