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XRCC1 plays a central role in mammalian DNA repair processes. Two polymorphisms of XRCC1, rs1799782 (Arg>Trp at codon 194) and rs25487 (Arg>Gln at codon 399), are common in the Han Chinese population. Our objective was to analyze the relationship between these two functional single-nucleotide polymorphisms (SNPs) and systemic lupus erythematosus (SLE) in the Taiwanese Han Chinese population. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) on 172 SLE patients and 160 normal controls. Our data indicate that the frequency of A/G at codon 399 differed between patients and controls (p=0.01; odds ratio: 1.80; 95% confidence interval: 1.17-2.75), but the allelic frequency analysis did not reveal significant differences. For the SNP at codon 194, there were no differences in either allelic or genotype frequencies between SLE patients and normal subjects. Clinical association studies of SLE symptoms revealed the involvement of the A/G polymorphism at codon 399 in SLE pathogenesis. Our results indicate that a functional SNP at codon 399 of XRCC1 is associated with the development of SLE. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor-α (TNF-α), an important proinflammatory cytokine, exerts a variety of physiological and pathogenic effects that lead to tissue destruction. Studies on the association of TNF-α genetic polymorphisms with systemic lupus erythematosus (SLE) have yielded inconclusive results. We investigated the association of TNF-α genetic polymorphisms (-1031T/C, -863C/A, -857T/C, -308A/G and +489A/G) with SLE in Taiwanese patients and controls. Our results indicate that 1) the frequency of the A-allele at -863 position was significantly higher in SLE patients (odds ratio = 1.46; 95% CI = 1.02-2.08); 2) the frequency of the A-allele at +489 position was significantly higher in SLE patients (odds ratio = 1.79; 95% CI = 1.21-2.65); 3) the AA or GA genotype frequencies at +489 position were significantly increased in SLE patients (AA genotype: odds ratio = 11.20; 95% CI = 1.36-92.55; GA genotype: odds ratio = 1.63; 95% CI = 1.03-2.58); 4) no significant association of TNF-α haplotypic distributions was observed, except for the haplotypes TCCGA, CACGA and CCCGG; and 5) the genotype frequency of the polymorphisms at -1031 was significantly different in patients with antinuclear antibodies (P = 0.022). The allele and genotype frequencies of the polymorphisms at -863 were not significantly different. The genotype frequency of the polymorphisms at -857 was significantly different in patients with haematological disorder (P = 0.025). The frequency of A allele of the polymorphisms at -308 was significantly increased in patients with malar rash (P = 0.033), discoid rash (P = 0.023), photosensitivity (P = 0.037), oral ulcers (P = 0.002) and serositis (P = 0.029). The genotype frequency of the polymorphisms at +489 was significantly different in patients with discoid rash and photosensitivity (data not shown; discoid rash, P = 0.031; photosensitivity, P = 0.044). These results suggest that TNF-α genetic polymorphisms contribute to SLE susceptibility in the Taiwanese population. [ABSTRACT FROM AUTHOR]

High expression of circulating vascular endothelial growth factor (VEGF) has been reported in patients with Kawasaki disease (KD). In the pathophysiology of KD, VEGF is considered to be involved, especially in the development of coronary artery lesions. This study aimed to examine whether the VEGF-634 promoter polymorphism is a marker of KD susceptibility or severity in Chinese patients in Taiwan. The study included 93 KD patients and 96 normal control subjects. Genotype and allelic frequencies for the VEGF gene polymorphism in the two groups were compared. The number of individuals with the VEGF-634 G/G genotype was significantly greater among the patients with KD than among the healthy control subjects ( p = 0.011). The odds ratio for the development of KD in individuals with the VEGF-634 G/G genotype was found to be 2.03 (95% confidence interval [CI], 1.14–3.63) compared with the VEGF-634 G/C and VEGF-634 C/C genotypes. No significant difference was observed in the genotype or allelic frequencies of VEGF C-634 G polymorphism between the patients with and those without coronary artery lesions. In conclusion, the results suggest that VEGF-634 G/G genotype may be involved in the development of KD in Taiwanese children. [ABSTRACT FROM AUTHOR]

Located between the South and the East China Sea, the Taiwan Straits (TWS) are a marine shelf-channel area, with unique hydrological and geomorphological features affected by rivers inflow and with recent algal blooms with red tide events. This study aimed at assessing microbial distribution and function and their modulation in response to environmental gradients. Surface (0.5 m) water samples from 16 stations along five north to south transects were collected; total prokaryotic abundance by epifluorescence microscope and carbon substrate utilization patterns by Biolog Ecoplates were estimated. Spatially, a patchy microbial distribution was found, with the highest microbial metabolic levels and prokaryotic abundance in the TWS area between Minjiang River estuary and Pingtan Island, and progressive decreases towards offshore stations. Complex carbon sources and carbohydrates were preferentially metabolized. This study provides a snapshot of the microbial abundance and activity in TWS as a model site of aquatic ecosystems impacted from land inputs; obtained data highlights that microbial metabolism is more sensitive than abundance to environmental changes., (© 2022. The Author(s).)

Background: This study aimed to investigate the risk of Parkinson's disease (PD) among patients with age-related macular degeneration (AMD) and its association with confounding comorbidities., Methods: A population-based retrospective cohort study was conducted using Longitudinal Health Insurance Database 2000 (LHID2000). We established AMD and non-AMD cohorts from January 1, 2000 to December 31, 2012 to determine the diagnosis of PD. A total of 20,848 patients were enrolled, with 10,424 AMD patients and 10,424 controls matched for age, sex, and index year at a 1:1 ratio. The follow-up period was from the index date of AMD diagnosis to the diagnosis of PD, death, withdrawal from the insurance program, or end of 2013. Multivariable Cox regression analysis was performed to examine the hazard ratio (HR) and 95% confidence interval (CI) for the risk of PD between the AMD and non-AMD cohorts., Result: After adjusting for potential confounders, there was a higher risk of developing PD in the AMD cohort than in the non-AMD cohort (adjusted HR = 1.35, 95% CI = 1.16-1.58). A significant association could be observed in both female (aHR = 1.42, 95% CI = 1.13-1.80) and male (aHR = 1.28, 95% CI = 1.05-1.57) patients, aged more than 60 years (60-69: aHR = 1.51, 95% CI = 1.09-2.09, 70-79: aHR = 1.30, 95% CI = 1.05-1.60; 80-100: aHR = 1.40, 95% CI = 1.01-1.95), and with more than one comorbidity (aHR = 1.40, 95% CI = 1.20-1.64). A significant association between increased risk of PD and AMD was observed among patients with comorbidities of osteoporosis (aHR = 1.68, 95% CI = 1.22-2.33), diabetes (aHR = 1.41, 95% CI = 1.12-1.78) and hypertension (aHR = 1.36, 95% CI = 1.15-1.62) and medications of statin (aHR = 1.42, 95% CI = 1.19-1.69) and calcium channel blocker (CCB) (aHR = 1.32, 95% CI = 1.11-1.58). The cumulative incidence of PD was significantly higher over the 12-year follow-up period in AMD cohort (log-rank test, p < 0.001)., Conclusions: Patients with AMD may exhibit a higher risk of PD than those without AMD., (© 2021. The Author(s).)

Background: There is growing evidence suggesting that air pollution may act as an important environmental risk factor in the development and aggravation of childhood atopic dermatitis (AD)., Methods: We collected data from the Taiwan National Health Insurance (NHI) research database and linked the data to the Taiwan Air Quality-Monitoring Database. From January 1, 2000 to December 31, 2012; children aged below 18 years were selected from the database and followed longitudinally until the diagnosis of AD, withdrawal from the NHI, or December 31, 2012. Children with missing data or those diagnosed with AD before enrolment in this study were excluded. We measured the incidence rate and hazard ratios (HRs) for AD and stratified them by quartiles (Q1-Q4) of air pollutant concentration. Multivariable Cox proportional hazards models were also applied by adjusting for age, sex, monthly income, and level of urbanization., Results: When compared with the concentrations of pollutants in the Q1 quartile, the adjusted HR for AD increased with an increase in the exposure concentrations of total hydrocarbons (THCs), non-methane hydrocarbons (NMHCs), and methane (CH 4 ) from 1.65 (95% confidence interval [CI]: 1.47-1.84) to 10.6 (95% CI: 5.85-7.07), from 1.14 (95% CI: 1.06-1.24) to 2.47 (95% CI: 2.29-2.66), and from 1.70 (95% CI: 1.52-1.89) to 11.9 (95% CI: 10.8-13.1), respectively. Patients exposed to higher levels of THCs, NMHCs, and CH 4 exhibited greater incidence rates of childhood AD., Conclusions: The present study demonstrated that exposure to higher concentrations of THCs, NMHCs, and CH 4 were associated with an increased risk of childhood AD., (© 2021. The Author(s).)

Objective: This study aimed to investigate the risk of Alzheimer's disease among patients with age-related macular degeneration and its association with confounding comorbidities., Method: This was a population-based, retrospective cohort study. By accessing data from the National Health Insurance Research Database of Taiwan, we identified 10,578 patients aged 50-100 years who were newly diagnosed with age-related macular degeneration between 2000 and 2012 and 10,578 non- age-related macular degeneration individuals. The comorbidities assessed were osteoporosis, diabetes, cirrhosis, cerebrovascular disease, chronic kidney disease, hypertension, hyperlipidemia, coronary artery disease, and chronic obstructive pulmonary disease., Results: Patients with age-related macular degeneration had a 1.23-fold increased risk of their condition advancing to Alzheimer's disease (aHR = 1.23, 95% CI = 1.04-1.46). The younger patients were diagnosed with age-related macular degeneration, the more likely patients got Alzheimer's disease (50-64 age group: aHR = 1.97, 95% CI = 1.04-3.73; 65-79 age group: aHR = 1.27, 95% CI = 1.02-1.58; 80-100 age group: aHR = 1.06, 95% CI = 0.78-1.45). In addition, there were significantly higher risks of Alzheimer's disease for patients with cirrhosis (aHR = 1.50, 95% CI = 1.09-2.06) in the age-related macular degeneration cohort than in the non-age-related macular degeneration cohort., Conclusion: Patients with age-related macular degeneration may exhibit a higher risk of Alzheimer's disease than people without age-related macular degeneration., Competing Interests: The authors have declared that no competing interests exist.

Abstract: The etiology of dental-supporting tissue diseases in children is multi factorial and not merely related to oral hygiene. Therefore, in the present study, we investigated the relationship between children <18 years old with allergic rhinitis (AR) and the risk of dental-supporting tissue diseases.Data from the National Health Insurance Research Database (NHIRD) of Taiwan were used to conduct a retrospective longitudinal cohort study. The study cohort comprised 378,160 patients with AR (AR group) and 378,160 patients without AR (non-AR group), who were selected through frequency matching based on age, sex, and the index year. The study patients were followed until dental-supporting tissue diseases occurrence, withdrawal from the National Health Insurance program, or December 31, 2013. Cox proportional hazards regression analysis was conducted to calculate the risk of dental-supporting tissue diseases in the AR group after adjustment for age, sex, and relative comorbidities.The adjusted HRs of periodontal, pulp, and periapical diseases in AR children were higher than those in the non-AR controls (1.51, 95% CI: 1.50 to 1.53; 1.06, 95% CI: 1.05 to 1.07, respectively). The AR to non-AR HRs of these inflammatory dental diseases were particularly higher in children <6 years old and in boys. The HRs of periodontal, pulp, and periapical diseases were greatest in those with >5 AR-related medical visits/year (5.57, 95% CI: 5.50 to 5.56; 4.06, 95% CI: 4.00 to 4.12, respectively).Children with AR had a greater risk of inflammatory dental-supporting tissue diseases, particularly those <6 years old with primary teeth, boys, and those with severe persistent AR., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Although studies have suggested environmental factors to be triggers of headache, the contribution of long-term air pollution exposure to recurrent headaches is poorly understood. Hence, we executed this nationwide cohort study to investigate associations between levels of ambient air pollutants and risks of recurrent headaches in children in Taiwan from 2000 to 2012. We used data from the Taiwan National Health Insurance Research Database and linked them to the Taiwan Air Quality Monitoring Database. Overall, 218,008 children aged < 18 were identified from 1 January 2000, and then followed until they were diagnosed by a physician for ≥3 times with recurrent headaches or until 31 December 2012. We categorized the annual average concentration of each air pollutant (fine particulate matter, total hydrocarbon, methane, sulfur dioxide, and nitrogen dioxide) into quartiles (Q1-Q4). We measured the incidence rate, hazard ratios (HRs), and the corresponding 95% confidence intervals for recurrent headaches. stratified by the quartiles. A total of 28,037 children (12.9%) were identified with recurrent headaches. The incidence rate and adjusted HR for recurrent headaches increased with higher-level exposure of air pollutants, except sulfur dioxide. We herein demonstrate that long-term ambient air pollutant exposure might be a risk factor for childhood recurrent headaches., Competing Interests: The authors declare no conflict of interest.

Objective: This study investigated the long-term rates of depression after oophorectomy for benign gynecological conditions with or without comorbidities., Materials and Methods: This retrospective cohort study examined data from the National Health Insurance Research Database (NHIRD) involving 8199 women aged ≥20 years who underwent unilateral or bilateral oophorectomy for benign gynecological conditions (cases) between 2000 and 2013 (index date). A second cohort consisted of 32,796 women who did not undergo oophorectomy (controls) who were matched 4:1 to cases by age and index year. The follow-up time was more than 10 years. For all participants, the analysis accounted for comorbidities including hypertension, diabetes mellitus, hyperlipidemia, stroke, chronic obstructive pulmonary disease (COPD), chronic liver disease and cirrhosis, chronic kidney disease, and anxiety. Crude hazard ratios, adjusted hazard ratios, and 95% confidence intervals (CIs) were calculated according to multivariable Cox proportional hazard regression models adjusting for age, comorbidity, and the combination of oophorectomy with one comorbidity., Results: Our results show that unilateral or bilateral oophorectomy, whether performed by laparotomy or laparoscopy, increases the overall risk of depression (aHR: 1.36, 95%CI: 1.19-1.55). Compared with controls, women aged <50 years had a significantly higher incidence of depression. Having diabetes (aHR: 1.66, 95%CI: 1.09-2.51), hypertension (aHR:1.56, 95%CI:1.14-2.14), hyperlipidemia (aHR: 1.46, 95%CI: 1.04-2.05), stroke (aHR: 1.91, 95%CI: 1.01-3.60), COPD (aHR: 2.06, 95%CI: 1.3-3.26), chronic liver cirrhosis (aHR: 1.99, 95%CI:1.52-2.61), or anxiety (aHR: 5.01, 95%CI: 3.74-6.70) increased higher risk of depression compared with not having these comorbidities after oophorectomy. The likelihood of depression was highest within the first 6 years following oophorectomy (3-5years:aHR:1.26, 95%CI:1.00-1.58)., Conclusions: Oopherectomy increases the overall risk of depression. We offer useful information for surgical decision-making and preoperative assessments of women undergoing oophorectomy. It is concluded that a synergistic effect exists between oophorectomy and the comorbidities. Post-surgery, physicians should carefully evaluate the risk of depression developing amongst women with comorbidities. A postoperative follow-up time of at least 6 years is recommended, as this period was associated with a significantly higher rate of depression during our over 10-year follow-up., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To evaluate the suicide rate among patients oophorectomized for benign conditions and its association with confounding comorbidities. Method: We conducted a population-based, retrospective cohort study of women aged ≥20 years that underwent oophorectomy including unilateral or bilateral in laparotomy or laparoscopy for benign conditions during 2000-2013. A total of 145,588 oophorectomized and 582,352 non-oophorectomized women were included with an average follow-up time of 7 years. The comorbidities assessed were hypertension (HTN), diabetes mellitus, hyperlipidemia, stroke, chronic obstructive pulmonary disease (COPD), chronic liver disease and cirrhosis, chronic kidney disease and anxiety disorder. Result: The overall suicide rate was significantly higher in the oophorectomized group. The rate among oophorectomized patients of 20-49 years was significantly greater than in non-oophorectomized patients of the same age group. Hypertension, COPD, anxiety disorder and chronic liver disease and cirrhosis were associated with a significantly higher suicide rate in oophorectomized women. A significant increase in suicide incidence was observed in patients with <6 years' follow-up. Conclusion: A significant increase in suicide rate among oophorectomized women aged 20-49 years was found. The decision to perform oophorectomy should be made cautiously, especially in patients with hypertension, COPD, chronic liver disease and cirrhosis or anxiety disorder. Patients should be followed for at least 6 years postoperatively since the suicide rate is significantly higher in this period.

Objectives: To evaluate the incidence of endometriosis among endometritis patients and its association with confounding comorbidities., Material and Methods: A population-based, retrospective cohort study of women aged between 20 to 55 years, who were newly diagnosed with endometritis between 2000 to 2013. A total of 16,830 endometritis patients and 67,230 non-endometritis individuals were enrolled by accessing data from the National Health Insurance Research Database of Taiwan. The comorbidities accessed were uterine leiomyoma, rheumatoid arthritis, ovarian cancer, infertility and allergic diseases., Results: The mean follow-up period was 9.15 years for the non-endometritis cohort and 9.13 years for the endometritis cohort. There were significantly higher percentages of uterine leiomyoma, rheumatoid arthritis, infertility, ovarian cancer and allergic diseases in the endometritis cohort than in the non-endometritis cohort. Patients with endometritis had a 1.5-fold increased risk of their condition advancing to endometriosis (HR 1.58, 95% CI 1.48-1.68)., Conclusions: Our results suggest that patients with endometritis exhibited a positive correlation in developing endometriosis.

Myopia is caused by complex genetic and environmental factors. However, information regarding the effect of long-term exposure to air pollutants on the risk of development of myopia is lacking. We collected data from two linked databases: the Taiwan National Health Insurance Research Database (NHIRD) and the Taiwan Air Quality-Monitoring Database (TAQMD). A total of 15,822 children (16.3%) were diagnosed with myopia within the cohort. The incidence rate of myopia increased with exposure to increasing concentrations of particulate matter (PM2.5) and nitrogen oxides (NOx), increasing from 15.8 to 24.5 and from 13.7 to 34.4, per 1000 person-years, respectively. The adjusted hazard ratio for myopia increased with elevated PM2.5 and NOx exposure concentrations in Q4 to 1.57 and 2.60, respectively, compared to those exposed to the corresponding concentrations in Q1. In the animal experiments, PM2.5 induced myopia in hamsters by enhancing inflammation and was inhibited by resveratrol treatment compared to the control group. The change in axial length in the PM2.5 group was 0.386 ± 0.069 mm versus 0.287 ± 0.086 mm in the control group and 0.257 ± 0.059 mm in the PM2.5 + resveratrol group. We provide both clinical and experimental correlations that exposure to ambient air pollutants is associated with the pathogenesis of myopia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: MUTYH glycosylase involved in DNA repair pathways may be associated with the risk of autoimmune diseases such as rheumatoid arthritis (RA). Therefore, the association between polymorphisms in the MUTYH gene and RA was evaluated., Methods: We recruited 192 RA patients and 192 healthy subjects in Taiwan. The 4 MUTYH polymorphisms (rs3219463, rs3219476, rs3219489, and rs3219493) were detected and haplotype analysis was performed using the Bayesian method. The genotype and allelic frequency distributions of the polymorphisms in both RA patients and healthy patients were compared by the chi-square test., Results: Comparison of the genotype/allele frequencies between individuals with RA and the control groups revealed significant differences in 2 MUTYH gene polymorphisms, rs3219463 and rs3219476. After we performed a haplotype-specific analysis, the haplotypes Ht6-GTGC and Ht8-GGCG had lower presenting rates in RA patients than in the control groups. Furthermore, the genotype frequency of rs3219463 G/  was significantly increased among patients with immunoglobulin M rheumatoid factors, whereas that of rs3219476 was not., Conclusion: We demonstrated that the rs3219463 and rs3219476 polymorphisms in RA patients from a Taiwan Chinese population were associated with disease susceptibility. These data indicate that the MUTYH gene may play a role in the progression of RA.

Graves' disease (GD) is a complex, organ-specific autoimmune disease wherein the thyroid gland becomes enlarged and overactive. During GD progression, T cells secrete interleukin-16 (IL-16) to promote inflammation, act as chemoattractants that recruit more inflammatory cells, and activate target cells to enhance the development of GD. To investigate the role of IL-16 in GD, we genotyped 474 patients with GD at 8 single-nucleotide polymorphisms (SNPs) in the IL-16 gene. The IL-16 SNP rs8028364 was found to be associated with GD when compared with the control subjects (P = 2.93 × 10⁻¹⁷; CG genotype: odds ratio [OR] = 0.2 [0.07, 0.59]; CC genotype: OR = 0.03 [0.01, 0.09]). The rs1131445 polymorphism was found to be associated with GD under the allelic model (P = 0.01; G allele: OR = 1.97 [1.17, 3.32]). Sliding-window haplotype analysis by the PLINK program showed that the most significant haplotype was provided by the 6-SNP haplotype window, consisting of rs7182786, rs8028364, rs12907134, rs4128767, rs4072111 and rs8031107 (P = 2.31 × 10⁻⁵¹). We found 2 protective haplotypes: GCAAGG (P = 8.69 × 10⁻⁷; OR = 0.22 [0.12, 0.41]) and AGAAGG (P = 0.0012; OR = 0.26 [0.12, 0.6]). In addition, GGGGAA (P = 0.39; OR = 2.32 [1.08, 4.99]) and GGGAGA (P = 1.18 × 10⁻⁵; OR = 5.54 [2.50, 12.31]) were found to be the two high-risk haplotypes. These results suggest that polymorphisms in IL-16 may be used as genetic markers for the diagnosis and prognosis of GD.

Background: Graves' disease (GD) and Graves' ophthalmopathy (GO) are autoimmune disorders, which might be influenced by genetic factors. Copy number variation (CNV) is an important source of genomic diversity in humans, and influences disease susceptibility. This study investigated the association between CNV in the TSHR and TLR7 genes and the development of GD and GO in a Chinese population in Taiwan., Methods: For this case-control study, sample from 196 healthy controls and 484 GD patients, including 203 patients with GO were studied. CNV was detected by real-time polymerase chain reaction (PCR) using TaqMan™ probes and the relative copy number (CN) was estimated by using the comparative Ct method., Results: The differences in the distribution of TSHR CNV in healthy controls and GD patients were statistically significant (p value = 0.01). However, the difference in the distribution of TSHR CNV in the control group and the GO group was not statistically significant (p value = 0.06). For TLR7 CNV, the results were not significantly different when we compared the distribution in healthy controls and GD patients and in healthy controls and GO patients (p values for Fisher's exact test were 0.13 and 0.09, respectively). However, a lower than normal CNV for TLR7 (CNV < 2 for female and CNV < 1 for male) was found to have a protective effect against the development of GD (odds ratio (OR) = 0.24; 95% confidence interval (CI), 0.07-0.75) after adjusting for age and gender., Conclusions: These results suggested that TSHR and TLR7 CNV might be associated with susceptibility to GD.

Genetic polymorphisms observed in various disease states associated with sensitivity or resistance to specific treatments have been a robust area of investigation for decades, with the potential to allow clinicians to make evidence-based decisions on the appropriate course of treatment. This study aimed to evaluate whether genetic polymorphisms of the signal transducer and activator of transcription 6 gene (STAT6) could be associated with a sustained virological response (SVR) among patients infected with hepatitis C virus genotypes 1 and 2 (HCV-1 and HCV-2) who were treated with peginterferon plus ribavirin (PEG-IFNα-RBV). We analyzed the associations between SVR to PEG-IFNα-RBV therapy and 4 single nucleotide polymorphisms (SNPs) in STAT6. This study included Taiwanese Chinese patients infected with either HCV-1 (n = 265) or HCV-2 (n = 195) in the presence or absence of an SVR. Among the STAT6 SNPs examined, the dosage effect of the A allele and allele frequency in rs1059513 were inversely correlated with SVR in patients infected with HCV-1 (P = 0.0179 and P = 0.0235, respectively). This effect was not observed in patients infected with HCV-2. The GG, GGG, and GGGC STAT6 haplotypes comprising 2, 3, and 4 SNPs (rs1059513, rs703817, rs324015, and rs3024974) were found to be associated with SVR, and their presence may increase the probability of a successful treatment outcome in patients infected with HCV-1 (P = 0.0273, 0.0352, and 0.0368, respectively). Moreover, a multivariate logistic regression model for predicting an SVR revealed that the presence of the GGGC haplotype carriers mutually affected the outcome of PEG-IFNα-RBV treatment. The presence of STAT6 SNPs and the association with SVR demonstrated that STAT6 polymorphisms might influence the therapeutic outcomes of patients infected with HCV-1 under standard-of-care (SOC) treatment.

The involvement of uracil-DNA glycosylase (UNG) in the pathogenesis of cancer is well documented. In contrast, the role of this protein in rheumatoid arthritis (RA) development is not well defined, although previous studies suggest a possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between UNG genetic polymorphisms and RA. Our present study investigated the effects of UNG (rs3219218 and rs246079) single nucleotide polymorphisms (SNPs) on RA among Taiwan's Han Chinese population. Polymorphism of the UNG gene was analyzed in 192 controls and 183 RA patients. Genotyping for UNG SNPs was performed by restriction fragment length polymorphism assay. Our data confirmed statistically significant variations in genotype frequency distributions at rs246079 SNP between RA patients and controls (P = 3.05 × 10(-4)). The G allele at rs246079 SNP is a high-risk factor in developing RA (odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.290-2.42). A comparison of haplotype frequencies between the case and the control revealed that RA patients with the Ht2 haplotype are at additional risk for RA development (P = 0.042). Our data yielded new information on UNG polymorphisms associated with RA development and as RA molecular markers. The polymorphisms revealed by the present study merit further investigation.

Background: The aim of this study was to evaluate whether polymorphisms in the guanine nucleotide binding (G protein), beta polypeptide 1 (GNB1) gene are associated with a rapid virological response (RVR) among HCV genotype 1 (HCV-1) and 2 (HCV-2) infected patients receiving peginterferon plus ribavirin treatment (PEG-IFNα-RBV)., Methods: We analyzed the association between RVR to PEG-IFNα-RBV therapy and 4 tagging single nucleotide polymorphisms (SNPs) of the GNB1 gene. This study included 265 HCV-1 and 195 HCV-2 infected patients in a Chinese population in Taiwan., Results: Among the GNB1 SNPs examined, the combination of genotypes G/G and G/T populations of rs12126768 was significant inversely correlated with RVR in HCV-1 infected patients (P = 0.0330), whereas HCV-2 infected patients, combination of A/A and A/C genotypes populations at rs4648727 responded better to the PEG-IFNα-RBV treatment (P = 0.0089). However, there were no significant differences in the allele frequencies of those SNPs between RVR responders and non-responders. Several RVR susceptibility GNB1 haplotypes were identified, and the ACAT haplotype of the 4 SNPs may increase the successful outcomes of HCV-1 and HCV-2 infected patients (P = 0.0261 and P = 0.0253, respectively)., Conclusion: The data for GNB1 SNPs and the association of RVR showed that GNB1 polymorphisms might be associated with the therapeutic outcomes of HCV-1 and HCV-2 infected patients under standard of care (SOC) treatment.

Background: Interleukin 12B (IL12B) gene polymorphisms have been linked to several inflammatory diseases, but their role in the development of Graves ophthalmopathy (GO) in Graves disease (GD) patients is unclear. The purpose of this study was to investigate the disease association of IL12B single nucleotide polymorphisms (SNPs)., Methods: A Taiwan Chinese population comprising 200 GD patients with GO and 271 GD patients without GO was genotyped using an allele-specific extension and ligation method. Hardy-Weinberg equilibrium was estimated using the chi-square test. Allele and genotype frequencies were compared between GD patients with and without GO using the chi-square test., Results: The genotype and allele frequencies of examined SNPs did not differ between GD patients with and without GO. Although the genotype distribution remained nonsignificant in the sex-stratified analyses, the frequency of the T allele at SNP rs1003199 was significantly higher in patients with GO in the male cohort (P = 6.00 × 10(-3)). In addition, haplotypes of IL12B may be used to predict the risk of GO (P = 1.70 × 10(-2)); however, we could not prove the statistical significance of analysis after applying the Bonferroni correction., Conclusions: Our results provide new information that the examined IL12B gene polymorphisms may be associated with susceptibility to GO in the Taiwan Chinese population in a sex-specific manner. This conclusion requires further investigation.

The involvement of the epidermal growth factor receptor (EGFR) in the pathogenesis of cancer is well documented. In contrast, its role in rheumatoid arthritis (RA) development is not that well defined although previous studies suggested the possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between the EGFR genetic polymorphisms and the RA. Our study gauged the effects of EGFR (rs11543848 and rs17337023) single-nucleotide polymorphisms (SNPs) on RA among Taiwan's Han Chinese population. Polymorphism of EGFR gene was analyzed in 188 RA patients and 128 control subjects. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. Our data confirmed statistically significant increased risk of RA development in subjects with A carrier at rs17337023 SNP (P < 0.0001), and subjects with A allele at rs17337023 SNP (odds ratio [OR] = 1.52; 95% confidence interval [CI] = 1.10-2.09). Furthermore, comparison of haplotype frequencies between patients and controls suggested GA and AT haplotypes were more "at-risk" for RA development (P < 0.0001 and P < 0.01, respectively). However, comparisons of the clinical features of RA patients according to different genotypes and haplotypes revealed no significant difference. In conclusion, our data yield the new information on EGFR polymorphisms (rs11543848 and rs17337023) with the susceptibility of RA development and polymorphism revealed by this study merit further investigation.

Rheumatoid arthritis (RA) is a chronic autoimmune disease and can lead to deformities and severe disabilities, due to irreversible damage of tendons, joints, and bones. Previous study indicated that DNA repair system was involved in the pathology of RA. In this study, we investigated the association of two 8-oxoguanine glycosylase 1 (OGG1) gene polymorphisms (rs159153 and rs3219008) with the susceptibility to RA in 384 Taiwanese individuals (192 patients with RA and 192 controls). Our data showed that statistically significant difference in genotype frequency distributions was found at rs3219008 SNP between patients with RA and control groups (P = 5.6E-0.5). Our data also indicated that individuals with the AG genotype at rs3219008 SNP may have a higher risk of developing RA. We did not observe any statistically significant association of OGG1 haplotype frequencies (rs159153 and rs3219008) with RA progression. The study suggested that OGG1 polymorphisms (rs159153 and rs3219008) are associated with RA progression and that these may be used as molecular markers of RA.

This study examines whether or not MBD4 polymorphism is a marker for rheumatoid arthritis (RA) susceptibility or severity for Chinese patients in Taiwan. This study included 193 patients with RA, while 190 unrelated healthy individuals living in Central Taiwan served as controls. The relationship between MBD4 polymorphism and clinical manifestations of RA was evaluated. For the genotype and allelic frequency of MBD4-1057 polymorphism, there were no statistically significant differences between patients with RA and controls. There were significant differences in the distribution of MBD4-8666 polymorphism frequencies between patients with RA and controls [P = 0.013; P (corrected) (Pc) = 0.039]. There were also significant relationships in the distribution of MBD4-9229 polymorphism genotype between patients with RA and controls (P = 0.007; Pc = 0.021). However, we did not detect any associations for MBD4-1057, MBD4-8666 or MBD4-9229 with rheumatoid factor presence, extra-articular involvement or bone erosion in patients with RA. Results suggest that MBD4-8666 and MBD4-9229, but not MBD4-1057, gene polymorphisms are related to RA in Chinese patients in Taiwan.

Background: Asthma, one major respiratory consequence, might be caused by a complex interaction between multiple candidate genes and environmental factors. Herein, we aimed to investigate whether Janus kinase (JAK)-1 gene polymorphisms are associated with asthma susceptibility., Materials and Methods: Patients were divided into two groups: (1) asthma (n=117) and (2) nonasthma (n=60). The JAK-1 polymorphisms (rs2780895, rs10789166, rs4916008, rs2780885, rs17127114, and rs3806277) were amplified by polymerase chain reaction and detected by electrophoresis after restriction enzyme (HpyCH4IV, Tsp45I, HpaII, XmnI, MspI, and HpaII) digestions. Genotypes, allelic frequencies, and association of haplotypes in both groups were compared., Results: JAK-1 rs2780895 gene polymorphism is associated with susceptibility to asthma. Distributions of JAK-1 rs2780895*CC/CT/TT and C/T allele in both groups are: (1) 80/4/16% and 82/18%; (2) 48/45/7% and 71/29%. Other 5 JAK-1 SNPs (rs10789166, rs4916008, rs2780885, rs17127114, and rs3806277) are not associated with asthma susceptibilities. Distributions of JAK-1 rs10789166*AA/AG/GG, rs4916008*CC/CT/TT, rs2780885*CC/CT/TT, rs17127114*AA/AG/GG, rs3806277*AA/AG/GG in both groups are: (1) 50/40/10%, 42/49/9%, 50/40/10%, 9/37/54%, 8/35/57%; (2) 43/50/7%, 40/50/10%, 50/43/7%, 7/48/45%, 6/42/52%. Haplotype analyses for JAK-1 gene polymorphisms (rs2780895-rs10789166-rs4916008-rs2780885-rs17127114-rs3806277) revealed that JAK-1 haplotypes are not associated with asthma susceptibilities., Conclusions: JAK-1 rs2780895 C-related genotype and allele are associated with higher susceptibility to asthma. JAK-1 rs10789166, rs4916008, rs2780885, rs17127114, and rs3806277 single-nucleotide polymorphisms are not associated with asthma development. Some JAK-related genetic variations might be associated with asthma pathogenesis, which deserve further surveys.

Background: The national hepatitis B (HB) vaccination program in Taiwan that began in 1984 has resulted in a significant reduction in the carrier rate among children. However, a significant proportion of Taiwanese neonatal HB immunization recipients have exhibited low anti-HBs titers that fall to non-protective or undetectable levels., Methods: We recruited 1677 entering freshman and graduate student participants at a Taiwanese university health center, grouped them into three age groups representing three stages of Taiwan's HB vaccination program, then conducted hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) serological surveillances for each individual. Univariate and multivariate regression analyses of clinical characteristics and Interleukin-10 (IL-10) genetic variations were also conducted., Results: A trend toward a decreasing HBsAg carrier rate was observed over the starting dates of the vaccination program (11.7%, 1.6% and 1.7% for age groups 1, 2 and 3, respectively), but we also observed an increasing rate of non-protective anti-HBs titers (15%, 26% and 50.3% for cohorts 1-3, respectively). The percentage of students with non-protective anti-HBs titers increased from 23.1% for students born in 1984, to 25.2% for those born in 1985, to 39.4% for birth-year 1986 students, to 45.7% for birth-year 1987 students, and to 56.5% for birth-year 1988 students. The risk for low anti-HBs titers increased concurrently with increases in systolic blood pressure (BP), the IL-10 ATA/ACC haplotype, and the IL-10 ATA present haplotype. Risk for low anti-HBs titers decreased with concurrent decreases in glucose ante cibum (AC, before meals) and the IL-10 ACC/ACC haplotype., Conclusions: These results suggest that the genetic determinants may also contribute to variations in anti-HBs titers in immune responses to HB vaccination., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: This study evaluates whether B7 molecules (CD80 and CD86) could be used as genetic markers for the development of Graves' ophthalmopathy (GO)., Design: Cross-sectional study., Participants: We included 471 patients with Graves' disease (GD; 200 patients with GO and 271 patients without GO) in a Chinese population in Taiwan., Methods: An endocrinologist with substantial experience in thyroid diseases identified GO. Blood samples were taken for DNA extraction from GD subjects. The gene polymorphism of CD80 and CD86 was genotyped by polymerase chain reaction in each patient., Main Outcome Measures: Genotypes of CD80 and CD86 polymorphism., Results: We found that the frequency of C allele at position rs&#95;9831894 of the CD86 gene is different in patients with GD (with and without GO; chi-square test, P = 0.0017). In addition, the multifactor dimensionality reduction method was used to identify the best gene-gene interaction to predict the risk of GO. We identified an interaction between CD80&#95;rs9289131 and CD86&#95;rs9872483 (sign test, P = 0.0010). Moreover, the G-A haplotype was shown to have a protective effect in the development of ophthalmopathy among patients with GD (odds ratio, 0.63; 95% confidence interval, 0.44-0.90). Moreover, among patients with GO, the patients carrying the G-A haplotype had a lower level of free thyroxine T(4) than those not carrying the G-A haplotype (P = 0.0001)., Conclusions: These results suggest that the polymorphisms of the CD86 gene may be used as genetic markers for making the diagnosis and prognosis of GO. Therefore, GO could be a disease with complex genetic factors, resulting from the existing gene-gene interaction found in the present study., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate whether variations in the IL1B gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease (GD)., Method: This case-control study included 471 Taiwan Chinese patients with GD (200 with GO and 271 without GO) and 160 healthy volunteers. Eight single-nucleotide polymorphisms (SNPs) in IL1B were genotyped with an allele-specific extension and ligation assay., Results: In the IL1B SNPs examined, the C allele of rs1143634 was associated with GD, whereas the T/T genotype of the SNPs rs1143634 and rs16944 were less associated with the disease. The A/A genotype of the SNPs rs3917368 and rs1143643, which had the strongest interaction, may increase the risk of GO (P = 0.024 and P = 0.017, respectively). Several GD susceptibility and insusceptibility IL1B haplotypes have been identified, and the Ht4-GCGCCTCC haplotype, composed of eight SNPs and associated with low circulating IL1β levels, may be protective against the development of GO (P = 0.025). Moreover, that the GO-susceptible genotype was associated with lower plasma IL1β concentrations implies that the origin of GO may go beyond the IL1B polymorphism-associated elevation of circulating IL1β., Conclusions: The data for IL1B polymorphisms and the association of GD and GO with plasma IL1β levels show that IL1B polymorphisms may be associated with the development of GD and GO.

Kawasaki disease (KD) is the most common form of pediatric vasculitis. Though its etiology is unknown, researchers have suggested that it is related to genetics. The inositol 1,4,5-triphosphate receptor type 3 (ITPR3) gene has a strong association with the development of type 1 diabetes and, plays a critical role in the development of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Graves' disease. The aim of study is to examine the association of ITPR3 polymorphisms with KD risk in Taiwanese children. This study evaluates the single nucleotide polymorphisms (SNP) rs2229634 in the ITPR3 gene with KD in a case-control study involving 93 KD patients and 680 healthy, gender- and age-matched controls. The frequency of the rs2229634 T/T genotype was significantly higher in KD patients with coronary artery aneurysm (CAA) than in patients without CAA [odds ratio (OR) = 2.56, 95% confidence interval (95% CI) = 1.35-4.88, P = 0.004]. In addition, KD patients with the T/T genotype elevated mean serum levels of C-reactive protein compared with patients with the C/C or C/T genotype (12.2 mg dL(-1) vs. 8.5 mg dL(-1) , P = 0.036). In conclusion, the results of this study suggest that the rs2229634 SNP in the ITPR3 gene is associated with the risk of CAA formation in Taiwanese KD patients., (© 2010 Blackwell Publishing Ltd.)

Background: Toll-like receptors (TLRs) are a family of pattern-recognition receptors, which plays a role in eliciting innate/adaptive immune responses and developing chronic inflammation. The polymorphisms of TLRs have been associated with the risk of various autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis and rheumatorid arthritis. The aim of this study was to evaluate whether TLR genes could be used as genetic markers for the development of Graves' ophthalmopathy (GO)., Methods: 6 TLR-4 and 2 TLR-9 gene polymorphisms in 471 GD patients (200 patients with GO and 271 patients without GO) from a Taiwan Chinese population were evaluated., Results: No statistically significant difference was observed in the genotypic and allelic frequencies of TLR-4 and TLR-9 gene polymorphisms between the GD patients with and without GO. However, sex-stratified analyses showed that the association between TLR-9 gene polymorphism and GO phenotype was more pronounced in the male patients. The odds ratios (ORs) was 2.11 (95% confidence interval [CI] = 1.14-3.91) for rs187084 AàG polymorphism and 1.97 (95% CI = 1.07-3.62) for rs352140 AàG polymorphism among the male patients. Increasing one G allele of rs287084 and one A allele of rs352140 increased the risk of GO (p values for trend tests were 0.0195 and 0.0345, respectively). Further, in haplotype analyses, the male patients carrying the GA haplotype had a higher risk of GO (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.09-3.73) than those not carrying the GA haplotype., Conclusion: The present data suggest that TLR-9 gene polymorphisms were significantly associated with increased susceptibility of ophthalmopathy in male GD patients.

Purpose: The purpose of this study was to investigate tumor necrosis factor-α gene polymorphisms in unrelated Taiwan Chinese patients with wet age-related macular degeneration (AMD) and controls., Methods: In this retrospective case-control study, we enrolled 190 wet AMD patients and 180 age- and gender-matched controls. Genomic DNA was extracted from the peripheral blood obtained from wet AMD patients and control subjects. Polymerase chain reaction was performed to analyze 6 candidate single nucleotide polymorphisms in the tumor necrosis factor-α gene: -238 G/A, -308 G/A, +489 G/A, -857 C/T, -863 C/A, and -1031 T/C., Results: Among the 6 candidate single nucleotide polymorphisms of the tumor necrosis factor-α gene, only -1031 T/C was significantly associated with wet AMD. The distribution of the -1031 T/C genotypes was significantly different between wet AMD patients (homozygous T [TT], 64%; TC heterozygous [TC], 36%; homozygous C [CC] 0%) and controls (TT, 66%; TC, 28%; CC, 7%; P = 7 × 10⁻⁴). The genotype CC of -1031 T/C was significantly lower than that in controls (0 vs. 7%, P = 1.45 × 10⁻⁴, odds ratio = 14.70, 95% confidence interval = 1.90-33.59). No single haplotype was found to be significantly associated with either wet AMD patients or controls., Conclusion: Our data indicate that the tumor necrosis factor-α -1031 T/C polymorphism may be associated with wet AMD in the Taiwan Chinese population.

Background: Idiopathic membranous nephropathy (IMN) is one of the most common forms of autoimmune nephritic syndrome in adults. The purpose of this study is to evaluate whether polymorphisms of PLA2R1 affect the development of IMN., Methods: Taiwanese-Chinese individuals (129 patients with IMN and 106 healthy controls) were enrolled in this study. The selected single nucleotide polymorphisms (SNPs) in PLA2R1 were genotyped by real-time polymerase chain reaction using TaqMan fluorescent probes, and were further confirmed by polymerase chain reaction-restriction fragment length polymorphism. The roles of the SNPs in disease progression were analyzed., Results: Genotype distribution was significantly different between patients with IMN and controls for PLA2R1 SNP rs35771982 (p = 0.015). The frequency of G allele at rs35771982 was significantly higher in patients with IMN as compared with controls (p = 0.005). In addition, haplotypes of PLA2R1 may be used to predict the risk of IMN (p = 0.004). Haplotype H1 plays a role in an increased risk of IMN while haplotype H3 plays a protective role against this disease. None of these polymorphisms showed a significant and independent influence on the progression of IMN and the risk of end-stage renal failure and death (ESRF/death). High disease progression in patients having C/T genotype at rs6757188 and C/G genotype at rs35771982 were associated with a low rate of remission., Conclusions: Our results provide new evidence that genetic polymorphisms of PLA2R1 may be the underlying cause of IMN, and the polymorphisms revealed by this study warrant further investigation.

Introduction: Systemic lupus erythematosus (SLE), a multisystemic autoimmune disease, is characterized by the production of a range of autoantibodies against nuclear constituents and other self-antigens. The studies in DNA repair deficiencies in SLE patients have been recently investigated., Aims: Few studies have been conducted on DNA repair gene polymorphisms and their role in autoimmune diseases. Our study purpose was to examine and compare NBS1 genotype distributions in a group of Taiwanese SLE patients and controls in Taiwan., Patients and Methods: Participants were Taiwanese SLE patients and healthy controls. We studied associations among NBS1 polymorphisms--rs1061302, rs709816, and rs1805794--considering clinical features for the entire group and stratified subgroups. No statistically significant differences between the patients and controls were noted. However, we observed significant decreases in Ht1-GGG, Ht2-AAC, and Ht3-AGC in the SLE patients (Ht1-GGG, OR = 0.26, 95% CI: 0.16-0.41; Ht2-AAC, OR = 0.30, 95% CI: 0.17-0.53; Ht3-AGC, OR = 0.35, 95% CI: 0.19-0.71) and significant increases in Ht4-AAG, Ht5-AGG, and Ht8-GGC among the SLE patients. Combined, these results suggest an association between NBS1 genetic polymorphisms and Taiwanese SLE patients.

Objective: To evaluate whether variations in the CD103 gene could be associated with Graves' ophthalmopathy (GO) in patients with Graves' disease., Design: Case-control study., Participants: A total of 484 Chinese patients with Graves' disease in Taiwan, including 203 patients with GO and 281 patients without GO, were enrolled., Methods: Five single nucleotide polymorphisms (SNPs) in CD103 were genotyped using an assay-on-demand allelic discrimination assay and detection system according to the manufacturer's instructions., Main Outcome Measures: Association of SNPs in CD103 with the development of GO., Results: The CD103 SNP rs11652878 was associated with GO, which may decrease the risk of GO by 1.57-fold (P = 0.029). The Ht5-GCGCG haplotype, composed of 5 SNPs in the CD103 gene (rs1716, rs3744679, rs11652878, rs16953477, and rs9905739), were protective haplotypes (P = 0.010). Moreover, the heterozygous genotype (Ht5/non-Ht5) was correlated with a reduced risk of GO and high grades of goiter as compared with the non-Ht5/non-Ht5 genotype (P = 0.006 and P = 0.048, respectively). Logistic analysis confirmed the contribution of CD103 rs11652878 to the protection of GO., Conclusions: These data suggest that patients with Graves' disease in the presence of the G allele of SNP rs11652878, especially Ht5-GCGCG, in CD103 are less susceptible toward the development of GO., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The butyrophilin-like 2 (BTNL2) gene is a member of the B7 receptor family that probably functions as a T cell costimulatory molecule. Because altered T cell functions are implicated in dysregulation of the immune response seen in Kawasaki disease (KD), it is reasonable to speculate that BTNL2 gene is involved in the pathophysiology of KD. The purpose of this study was to investigate whether polymorphisms of the BTNL2 gene are associated with KD and the development of coronary artery lesions (CALs) in Taiwanese children. Nine-three patients with KD and 669 ethnically matched healthy controls were genotyped for BTNL2 gene rs1555115 C/G and rs2395158 A/G polymorphisms. The frequency of GG genotype of rs 1555115 was significantly higher in KD patients compared with controls (2.2% vs 0.2%, P = 0.012). The odds ratio for developing KD in individuals with rs 1555115 GG genotype was 14.7 (95% confidence interval, 2.04-105.5, P = 0.003) compared with individuals with rs 1555115 CG and CC genotypes. No significant difference was observed in the genotype and allelic frequencies of rs 2395158 polymorphism between KD patients and controls. However, the frequency of the G allele of rs 2395158 was significantly higher in KD patients with CALs than in those without CALs (P = 0.001). No significant difference was observed in the genotype and allelic frequencies of rs 1555115 polymorphism between KD patients with and without CALs. In conclusion, our results suggest that BTNL2 gene polymorphisms might be genetic markers of KD susceptibility and risk of coronary artery complication in Taiwanese children.

Objectives: The genetic control of Interleukin-10 (IL-10) and Tumour necrosis factor-alpha (TNF-alpha) production and the possible interaction between the two cytokines in influencing SLE susceptibility as well as clinical features has not been completely evaluated in the Taiwanese population., Methods: We investigated the association of IL-10 and TNF-alpha promoter polymorphisms (-1082, -819 and -592 for IL-10 gene; -308 for TNF-alpha gene) with SLE in a total of 172 Taiwanese patients and 215 controls., Results: Our results indicate that IL-10 A/T/A-A/T/A genotype was associated with Taiwanese SLE, whereas no significance was observed between TNF-alpha genotype and SLE. Furthermore, the TNF-alpha G allele frequency of the polymorphism at -308 was significantly decreased in patients with oral ulcers. The combined frequencies of IL-10 A/T/A haplotype and TNF-alpha G-G genotype were significantly increased in SLE patients. In addition, the combined frequencies of IL-10 A/T/A haplotype and TNF-alpha G-G genotype were significantly decreased in patients with oral ulcers., Conclusions: These results suggest a significant correlation of the combined IL-10 and TNF-alpha genetic polymorphisms contribute to SLE susceptibility and clinical features in the Taiwanese population.

The epsilon chain of membrane-bound IgE (mIgE) is expressed predominantly as a "long" isoform, containing an extra segment of 52 amino acid (a.a.) residues, referred to as C epsilon mX, between the CH4 domain and the C-terminal membrane-anchoring transmembrane peptide. C epsilon mX results from an alternative splicing of the epsilon RNA transcript at 156-bp upstream of the splicing acceptor site used by the "short" isoform. Here, based on an analysis of the C epsilon mX genomic DNA sequences of 320 subjects residing in Taiwan, we report that single-nucleotide polymorphisms have been found at two positions, namely, G/T at #46 and A/G at #93 (along the 156 bp of C epsilon mX), with the former creating an amino acid change from Val to Leu at #16 (along the 52 a.a. of C epsilon mX) and the latter resulting in no change (Gly). Among the 640 C epsilon mX sequences identified, the previously known 46G93A allelic form appeared 293 times, the newly discovered 46T93A allelic form (GeneBank accession no. GU208817) 26 times, and the 46G93G allelic form (GU208818) 321 times. No 46T93G allelic form was found. Serum IgE measurements showed that the polymorphisms did not correlate with the levels of serum IgE. The anti-C epsilon mX monoclonal antibody, 4B12, could bind equally well to mIgE.Fc(L)(16V) and mIgE.Fc(L)(16L). While genetic variation of C epsilon mX of broader populations should also be investigated, these newly discovered genetic variants of C epsilon mX in the Taiwanese population do not seem to affect the feasibility of using an anti-C epsilon mX mAb, such as 4B12, to target mIgE-expressing B cells.

Background: Tricyclic antidepressants (TCA) were used to treat nocturnal enuresis (NE) for decades of years although their real mechanisms are unknown. Recently, some case studies demonstrated the efficacy of selective serotonin reuptake inhibitors (SSRI) in the treatment of NE. Both TCA and SSRI have similar influences on serotonin transmission. This study was aimed at evaluating whether 5-hydroxytryptamine receptor 2A (5HTR2A) gene is associated with NE., Methods: We analyzed rs6313 polymorphism in 5HTR2A gene of 213 Taiwanese children (116 NE cases and 97 healthy control subjects) using polymerase chain reaction-restriction fragment length polymorphism., Results: There were no significant differences when comparing the genotypes and allelic frequencies of rs6313 polymorphism in 5HTR2A gene between patients with NE and control subjects. However, when subsequently comparing 5HTR2A genotypes and allelic frequencies in NE child with different phenotypes, genotypes TT and TC appeared higher risks of polysymptomatic NE compared with CC (odds ratio (OR)=10.71, 95% confidence interval (CI)=2.66-43.12; OR=2.68, 95% CI=0.67-10.75, respectively; P=0.0002); and allele T also revealed higher frequencies of polysymptomatic NE compared with allele C (OR=3.7, 95% CI=2.01-6.79, P=0.000015)., Conclusions: This is the first study that shows the association between 5HTR2A gene polymorphisms and polysymptomatic NE. These results provide further evidence suggesting that genetic variations at 5HTR2A may influence NE treatment response., (© 2010 Wiley-Liss, Inc.)

Rheumatoid arthritis (RA) is a chronic autoimmune disease and can lead to deformities and severe disabilities, due to irreversible damage of tendons, joints, and bones. A previous study indicated that a DNA repair system was involved in the development of RA. In this study, we investigated the association of four N-methylpurine-DNA glycosylase (MPG) gene polymorphisms (rs3176364, rs710079, rs2858056, and rs2541632) with susceptibility to RA in 384 Taiwanese individuals (192 RA patients and 192 control subjects). Our data show a statistically significant difference in genotype frequency distributions at rs710079 and rs2858056 SNPs between RA patients and control groups (P = 0.040 and 0.029, respectively). Our data also indicated that individuals with the GG genotype at rs2858056 SNP may have a higher risk of developing RA. In addition, compared with the haplotype frequencies between case and control groups, individuals with the GCGC haplotype appeared to be at a greater risk of RA progression (P = 0.003, OR = 1.75; 95&percnt; CI = 1.20-1.55). Our results suggest that rs710079 and rs2858056 polymorphisms and the GCGC haplotype in the MPG gene are associated with the risk of RA progression, and thus may be used as molecular markers of RA if they are confirmed by further research.

Tumour necrosis factor-alpha (TNF-alpha), an important proinflammatory cytokine, exerts a variety of physiological and pathogenic effects that lead to tissue destruction. Studies on the association of TNF-alpha genetic polymorphisms with systemic lupus erythematosus (SLE) have yielded inconclusive results. We investigated the association of TNF-alpha genetic polymorphisms (-1031T/C, -863C/A, -857T/C, -308A/G and +489A/G) with SLE in Taiwanese patients and controls. Our results indicate that 1) the frequency of the A-allele at -863 position was significantly higher in SLE patients (odds ratio = 1.46; 95% CI = 1.02-2.08); 2) the frequency of the A-allele at +489 position was significantly higher in SLE patients (odds ratio = 1.79; 95% CI = 1.21-2.65); 3) the AA or GA genotype frequencies at +489 position were significantly increased in SLE patients (AA genotype: odds ratio = 11.20; 95% CI = 1.36-92.55; GA genotype: odds ratio = 1.63; 95% CI = 1.03-2.58); 4) no significant association of TNF-alpha haplotypic distributions was observed, except for the haplotypes TCCGA, CACGA and CCCGG; and 5) the genotype frequency of the polymorphisms at -1031 was significantly different in patients with antinuclear antibodies (P = 0.022). The allele and genotype frequencies of the polymorphisms at -863 were not significantly different. The genotype frequency of the polymorphisms at -857 was significantly different in patients with haematological disorder (P = 0.025). The frequency of A allele of the polymorphisms at -308 was significantly increased in patients with malar rash (P = 0.033), discoid rash (P = 0.023), photosensitivity (P = 0.037), oral ulcers (P = 0.002) and serositis (P = 0.029). The genotype frequency of the polymorphisms at +489 was significantly different in patients with discoid rash and photosensitivity (data not shown; discoid rash, P = 0.031; photosensitivity, P = 0.044). These results suggest that TNF-alpha genetic polymorphisms contribute to SLE susceptibility in the Taiwanese population.

Elevated serum levels of interleukin-10 (IL-10) have been reported in patients with Kawasaki disease (KD). IL-10 reduces the inflammatory actions of macrophages and T cells and it may play a significant role in the regulation of inflammatory vascular damage associated with systemic vasculitis. The aim of this study was to examine whether -592 IL-10 promoter polymorphism is a susceptibility or severity marker of KD in Chinese patients in Taiwan. The study included 105 KD patients and 100 normal controls. Genotype and allelic frequencies for the IL-10 gene polymorphism in both groups were compared. There were no significant between-group differences in the genotype distribution of IL-10 A-592C gene polymorphism (P=0.08). However, the frequency of the -592*A allele was significantly increased in the patients with KD compared with controls (71.9% vs. 61.0%, P=0.019). The odds ratio for developing KD in individuals with IL-10-592*A allele was 1.64 (95% confidence interval, 1.06-2.52) compared to individuals with the IL-10-592*C allele. No significant difference was observed in the genotype and allelic frequencies for the IL-10 A-592C polymorphism between patients with and without coronary artery lesions. The IL-10-592*A allele may be involved in the development of KD in Taiwanese children.

Objective: Kawasaki disease (KD) is a pediatric systemic vasculitis of unknown cause for which a genetic influence is supposed. The purpose of this study was to identify possible genetic variants in the major histocompatibility complex (MHC) region that are associated with KD and the development of coronary artery aneurysms (CAAs) in a Taiwanese population., Methods: The 168 genetic variants covering the MHC locus were analyzed in an association study of a Taiwanese cohort of 93 KD patients and 680 unrelated healthy children matched for sex and age with the study patients., Results: Eleven single-nucleotide polymorphisms (SNPs) were associated with the occurrence of KD. The SNP located at the 3'-untranslated region of HLA-E (rs2844724) was highly associated (P < 1 x 10(-7)). In addition, the frequency of the C allele was higher in KD patients without CAAs than in controls (P < 0.001) due to a significantly increased frequency of the CC and CT genotypes. Plasma levels of soluble HLA-E were significantly higher in KD patients than in controls regardless of the presence of CAAs. Furthermore, there was a trend toward higher plasma levels of soluble HLA-E in KD patients with the CT and TT genotypes of the HLA-E gene polymorphism., Conclusion: Our results suggest that the HLA-E gene polymorphism may play a role in the pathogenesis of KD.

Objective: To investigate a nosocomial outbreak of infection with multidrug-resistant (MDR) Acinetobacter baumannii in the intensive care units at China Medical University Hospital in Taiwan., Design: Prospective outbreak investigation., Setting: Three intensive care units in a 2,000-bed university hospital in Taichung, Taiwan., Methods: Thirty-eight stable patients in 3 intensive care units, all of whom had undergone an invasive procedure, were enrolled in our study. Ninety-four A. baumannii strains were isolated from the patients or the environment in the 3 intensive care units, during the period from January 1 through December 31, 2006. We characterized A. baumannii isolates by use of repetitive extragenic palindromic-polymerase chain reaction (REP-PCR) and random amplified polymorphic DNA (RAPD) fingerprinting. The clinical characteristics of the source patients and the environment were noted., Results: All of the clinical isolates were determined to belong to the same epidemic strain of MDR A. baumannii by the use of antimicrobial susceptibility tests, REP-PCR, and RAPD fingerprinting. All patients involved in the infection outbreak had undergone an invasive procedure. The outbreak strain was also isolated from the environment and the equipment in the intensive care units. Moreover, an environmental survey of one of the intensive care units found that both the patients and the environment harbored the same outbreak strain., Conclusion: The outbreak strain of A. baumannii might have been transmitted among medical staff and administration equipment. Routine and aggressive environmental and equipment disinfection is essential for preventing recurrent outbreaks of nosocomial infection with MDR A. baumannii.

Interleukin-18 (IL-18)-656T/G, -607A/C, and -137C/G promoter polymorphisms had been reported associated with Kawasaki disease (KD). An IL-18 genetic A/C polymorphism at coding position 105 (rs549908) has been linked with asthma, rheumatoid, and systemic lupus erythematosus. We tested a hypothesis that the IL-18 105A/C genetic polymorphism confers KD susceptibility. Study participants were Taiwanese KD patients and a healthy control group. Our data indicated that the frequency of C allele was significantly higher in the patient group (13.9%) than in the control group (2.7%; P<0.0001, odds ratio [OR]=5.93; 95% confidence interval [CI]=2.57-13.73). Therefore, persons with the C allele may have higher risk of developing KD. In addition, compared with the haplotype frequencies between case and control groups, the KD patients with TACC haplotype appeared to be a significant "at-risk" haplotype compared with other haplotypes (OR: 4.62, 95% CI: 1.71-12.43; P=0.001). KD patient with the TAGA haplotype appeared to be a significant "protective" haplotype compared with other haplotypes (OR: 0.51, 95% CI:0.29-0.89; P=0.017). Our results suggest that 105A/C polymorphism and the haplotypes in IL-18 gene are associated with the risk of KD in Taiwanese population., ((c) 2009 Wiley-Liss, Inc.)

Interleukin-2 (IL-2), one of the crucial immunoregulatory cytokines required for T lymphocyte activation, plays an important role in autoimmune diseases. An IL-2 genetic G/T polymorphism (rs2069763) has been linked with multiple sclerosis and rheumatoid arthritis. We tested a hypothesis that this polymorphism confers systemic lupus erythematosus (SLE) susceptibility. Study participants were Han Chinese SLE patients and a healthy control group in Taiwan. Our results indicate (a) a significantly higher G allele frequency in SLE patients (P=1.91 x 10(-14); OR=3.94; 95% CI=2.74-5.66), (b) a significantly higher G allele frequency in SLE patients with antinuclear antibodies (ANA) (P=0.033; OR=4.21; 95% CI=1.01-17.51) and (c) a significantly lower G allele frequency in SLE patients with discoid rash (P=0.019; OR=0.41; 95% CI=0.19-0.88). Our results suggest that this polymorphism may be involved in the genetic background of Taiwanese SLE.

Objective: Proinflammatory cytokines such as interferon-gamma (IFN-gamma) play an important role in the pathogenesis of Kawasaki disease (KD). Interleukin 18 (IL-18) plays a pivotal role in the T helper 1 (Th1)-type response, principally owing to its ability to induce IFN-gamma production. We assessed potential associations between functional IL-18 gene promoter polymorphisms and susceptibility to KD, in addition to clinical features of KD in individuals from Taiwan., Methods: One hundred forty-six patients with KD and 136 ethnically matched controls from the same geographic area were genotyped for IL-18 -656T/G, -607A/C, and -137C/G promoter polymorphisms., Results: No significant differences in allele and genotype frequencies were found between KD patients and controls for any of the IL-18 polymorphisms investigated. When we compared the overall distribution of haplotype frequencies between KD patients and controls, a significant difference was observed (p <0.0001). In addition, the frequency of the GCG haplotype was significantly higher (p = 0.00001, pc = 0.00004; OR 20.8, 95% CI 3.05-142.3), whereas the frequency of the TAG haplotype was significantly lower in KD patients compared with controls (p = 0.0001, pc = 0.0004; OR 0.35, 95% CI 0.19-0.61). No significant associations were found for comparisons of KD patients to those with and without coronary artery lesions., Conclusion: Our results suggest a potential implication of IL-18 promoter polymorphisms in susceptibility to KD in Taiwan.

Purpose: To investigate vascular endothelial growth factor (VEGF) gene polymorphisms in unrelated Taiwan Chinese patients with late age-related macular degeneration (AMD) and controls., Design: Retrospective case-control study., Methods: We enrolled 190 late AMD patients and 180 age-matched and gender-matched controls. Late AMD was classified as either dry (atrophic; grade 4) or wet (neovascular; grade 5) according to the International Age-Related Maculopathy Epidemiologic Study. Genomic deoxyribonucleic acid was prepared from peripheral blood obtained from all subjects. Polymerase chain reactions were used to analyze five candidate single-nucleotide polymorphisms (SNPs) in VEGF gene: +405C/G (rs2010963), -460 T/C (rs833061), +674 C/T (rs1413711), +936C/T (rs3025039), and -2578C/A (rs699947)., Results: Of the 190 late AMD patients, dry AMD was diagnosed in 104 and wet AMD in 86. Among the five candidate SNPs studied, only the +936 C/T was significantly associated with wet AMD (T allele: 30% in wet AMD vs 14% in controls; P = 1.45 x 10(-5); odds ratio, 2.61; 95% confidence interval, 1.68 to 4.07). No single haplotype was significantly associated with either late AMD or controls. Based on genotypes at both VEGF +936 C/T and the complement factor H (CFH) Y402H (rs1061170), the association of VEGF +936 C/T to AMD was significant when analyzed conditional on the presence of the CFH C risk allele and vice versa (P < .0001). The VEGF +936 C/T was in strong linkage disequilibrium with CFH Y402H (D' = 0.99)., Conclusions: Both VEGF +936 C/T and CFH Y402H polymorphisms are dependently associated with wet AMD in the Taiwan Chinese population.

Glycogen-storage disease type II (GSDII; OMIM #232300), an autosomal recessive disorder caused by a deficiency of the glycogen hydrolysis enzyme acid alpha-glucosidase (acid GAA; acid maltase, EC. 3.2.10.20), results in the accumulation of glycogen in the lysosome. We performed a molecular genetic study on 29 patients with infantile-onset glycogen-storage disease type II (GSDII), 6 with juvenile-onset GSDII and one carrier for GSDII. Seventeen different mutations were identified among them; 8 were novel mutations: c.421C > A (p.L141M), c.872T > C (p.L291P), c.893A > C (p.Y298S), c.1375G > A (p.D459N), c.1437G > C (p.K479N), c.1509&#95;1511del (p.A504del), c.1960T > C (p.S654P), and c.2174G > C (p.R725P). One of the mutations identified, c.2238G > C (p.W746C), which was a sequence change of unknown pathogenic significance causing diminished enzyme activity,was found homozygously in a juvenile-onset patient. We also found a juvenile-onset patient with homozygote c.1935C > A mutation which was frequently found in infantile-onset patients. In addition to mutations, we also identified 14 new polymorphisms in the acid alpha-glucosidase gene. The genotype/phenotype correlations indicated that c.2238G > C (p.W746C) is correlated with juvenile- onset GSDII and that c.872T > C (p.L291P) and c.1411&#95;1414del (p.E471fsX5) are correlated with infantile-onset GSDII. Mutational analysis of GAA is useful in genetic counseling and prenatal diagnosis of the disease.

Purpose: To investigate the Met72Thr (T/C) polymorphism (rs1136287) of pigment epithelium-derived factor (PEDF) gene exon 3 in unrelated Taiwan Chinese patients with late age-related macular degeneration (AMD) and control subjects without AMD., Design: Retrospective case-control study., Methods: We enrolled 190 unrelated Taiwan Chinese patients with late AMD and 90 age- and gender-matched control subjects. Grading of late AMD was classified based on a standardized set of diagnostic criteria established by the International Age-Related Maculopathy Epidemiologic Study. Late AMD was classified as either atrophic (dry, grade 4) or neovascular (wet, grade 5). Atrophic AMD refers to dry late-stage AMD without neovascularization, and wet AMD refers to neovascular AMD. Genomic deoxyribonucleic acid was prepared from peripheral blood obtained from all AMD patients and control subjects. Polymerase chain reaction analysis was used to analyze this polymorphism., Results: Of the 190 participants with late AMD, atrophic AMD was diagnosed in 104 patients and wet AMD was diagnosed in 86 patients. The genotype distribution of the Met72Thr (T/C) variant of PEDF was TT (homozygous T), TC (heterozygous), and CC (homozygous C). The T allele was found significantly more frequently in wet AMD patients than in controls (50% vs 31%; P =.0005). The allele frequencies in atrophic AMD (30%) and controls (31%) did not differ significantly (all P = .87). The homozygous T genotype was more prevalent in wet AMD than in controls (26/86 [30%] vs nine/90 [10%]; odds ratio, 3.9; all P = .0015). The homozygous T genotype in atrophic AMD patients (8%) and controls (10%) did not differ significantly (all P = .75)., Conclusions: Our data suggest that the PEDF Met72Thr T allele may be a risk factor for wet AMD in the Taiwan Chinese population. PEDF may play a role in the pathogenesis of wet AMD.

Purpose: To investigate polymorphisms in a candidate gene of interleukin (IL) in unrelated Taiwan Chinese patients with late age-related macular degeneration (AMD) and control subjects without AMD., Methods: In this retrospective, case-control study, 312 unrelated Taiwan Chinese patients with late AMD and 180 age- and sex-matched control subjects were enrolled. Late AMD was classified as either atrophic (dry) or neovascular (wet) according to the International ARM Epidemiologic Study. Genomic DNA was prepared from peripheral blood obtained from all patients with AMD and control subjects. Polymerase chain reactions were used to analyze 14 single-nucleotide polymorphisms (SNPs) in candidate genes of 5 ILs: IL-1beta(2q14): -511 T/C; IL-6 (7p21): -572 C/G and -596 G/A; IL-8 (4q13-q21): -251 A/T, +781 C/T, +1633 T/C, and +2767 A/T; IL-10 (1q31-q32): -592 A/C, -819 C/T, and -1082 G/A; and IL-18 (11q22.2-q22.3): +105 A/C, -137 C/G, -607 A/C, and -656 T/G., Results: In the 312 patients with late AMD, dry AMD was diagnosed in 136 and wet AMD in 176. Among the 14 SNPs in the 5 IL genes studied, only the IL-8 +781 C/T SNP was significantly associated with wet AMD (T allele: 46% in wet AMD versus 28% in the control subjects, P = 1.03 x 10(-6), OR = 2.16, 95% CI = 1.58-2.94). The association analysis based on genotypes at both IL-8 +781 C/T and the CFH Y402H demonstrated that the IL-8 +781 C/T to AMD was not significant when analyzed conditional on the presence of the CFH Y402H C risk allele and vice versa. The IL-8 +781 C/T was in low linkage disequilibrium with CFH Y402H (D' = 0.02)., Conclusions: The data suggest that Taiwan Chinese carriers of the IL-8 +781 T allele, independent of the CFH Y402H polymorphism, are at increased risk of developing wet AMD.

Purpose: To investigate HTRA1 polymorphisms in unrelated Taiwan Chinese patients with age-related macular degeneration (AMD) and control subjects without AMD., Methods: A total of 95 unrelated Taiwan Chinese patients with AMD and 90 age- and sex-matched control subjects were enrolled in the study. Genomic DNA was prepared from peripheral blood obtained from all patients with AMD and control subjects. Polymerase chain reactions were used to analyze two HTRA1 single-nucleotide polymorphisms (rs11200638 [G/A] and rs10490924 [G/T])., Results: Of the 95 participants with AMD, dry AMD was diagnosed in 52 patients and wet AMD in 43 patients. Both rs11200638 (G/A) and rs10490924 (G/T) were significantly associated with all AMD (rs11200638: P = 6.7 x 10(-7) for an additive allele-dosage model, OR(het) = 1.97 [0.81, 4.81], OR(hom) = 8.59 [3.28, 22.49], A allele: 73% in all AMD versus 47% in controls; rs10490924: P = 9.2 x 10(-6), OR(het) = 1.86 [0.79, 4.35], OR(hom) = 5.08 [2.21, 11.70], T allele: 73% in all AMD versus 50% in controls). In terms of significance of association, rs11200638 was the most significantly associated variant. Subtype analysis including dry and wet AMD also revealed similar results. Haplotype analysis demonstrated that AT was significantly associated with wet and all AMD (P = 0.011 and 0.004, respectively), whereas GG was significantly associated with the control group when compared with all AMD (P = 0.035)., Conclusions: The study demonstrated that both single-nucleotide polymorphisms were significantly associated with dry and wet AMD and rs11200638 was the most significantly associated variant in a Taiwan Chinese population.