Wei Pin Chang

ITPKC single nucleotide polymorphism associated with the Kawasaki disease in a Taiwanese population.

Kawasaki disease (KD) is characterized by systemic vasculitis with unknown etiology. Previous studies from Japan indicated that a gene polymorphism of ITPKC (rs28493229) is responsible for susceptibility to KD. We collected DNA samples from 1,531 Taiwanese subjects (341 KD patients and 1,190 controls) for genotyping ITPKC. In this study, no significant association was noted for the ITPKC polymorphism (rs28493229) between the controls and KD patients, although the CC genotype was overrepresented. We further combined our data with previously published case/control KD studies in the Taiwanese population and performed a meta-analysis. A significant association between rs28493229 and KD was found (Odds Ratio:1.36, 95% Confidence Interval 1.12–1.66). Importantly, a significant association was obtained between rs28493229 and KD patients with aneurysm formation (P = 0.001, under the recessive model). Taken together, our results indicated that C-allele of ITPKC SNP rs28493229 is associated with the susceptibility and aneurysm formation in KD patients in a Taiwanese population.

CASP3 gene single-nucleotide polymorphism (rs72689236) and Kawasaki disease in Taiwanese children

Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. A study from Japan reported that G to A substitution of a single-nucleotide polymorphism (SNP) located in the 5′-untranslated region of caspase 3 (CASP3) (rs72689236), which was associated with nuclear factor of activated T cell-mediated T-cell activation, is responsible for susceptibility to KD. This study was conducted to investigate whether the polymorphism of CASP3 is responsible for susceptibility and coronary artery lesion (CAL) formation in KD in the Taiwanese population. A total of 1092 subjects (341 KD patients and 751 controls) were investigated to identify an SNP of rs72689236 using Invader assays (Third Wave Technologies). Our data provided a borderline significant association between the genotypes and allele frequency of rs72689236 in control subjects and KD patients (P=0.0535 under the dominant model; P=0.0575 under the allelic model). The A allele of rs72689236 in KD patients and in patients with CAL and intravenous immunoglobulin resistance was seen in a higher frequency. Importantly, a significant association was obtained between rs72689236 and KD patients with aneurysm formation (P=0.009, under the recessive model). The A allele of rs72689236 is very likely to be a risk allele in the development of aneurysm in patients with KD.

Sleep apnea and the subsequent risk of breast cancer in women: a nationwide population-based cohort study

BACKGROUND Hypoxia plays an important role in the development of solid tumors. Intermittent hypoxia is the hallmark of sleep apnea (SA). We tested the hypothesis that SA may increase the risk of breast cancer in Taiwan by using a population-based data set. METHODS Our study cohort consisted of women diagnosed with SA between January 2003 and December 2005 (n = 846). For each SA patient, five age-matched control women were randomly selected as the comparison cohort (n = 4230). All participant cases were followed for 5 years from the index date to identify the development of breast cancer. Cox proportional-hazards regression was performed to evaluate the 5-year breast-cancer-free survival rates. RESULTS Forty-four women developed breast cancer during the 5-year follow-up period, among whom 12 were SA patients and 32 were in the comparison cohort. The adjusted hazard ratio (HR) of breast cancer in patients with SA was higher [HR, 2.09; 95% confidence interval (CI), 1.06-4.12; P < 0.05] than that of the controls during the 5-year follow-up. Despite not meeting statistical significance, we found increases in the risk of breast cancer in women aged 30-59 years (HR, 2.06; 95% CI, 0.90-4.70) and ≥60 years (HR, 3.05; 95% CI, 0.90-10.32) compared with those aged 0-29 years. CONCLUSION The findings of our population-based study suggest an association between SA and an increased risk of breast cancer in women.

ORAI1 Genetic Polymorphisms Associated with the Susceptibility of Atopic Dermatitis in Japanese and Taiwanese Populations

Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.

Association of ORAI1 Haplotypes with the Risk of HLA-B27 Positive Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic inflammation of the sacroiliac joints, spine and peripheral joints. The aetiology of ankylosing spondylitis is still unclear. Previous studies have indicated that genetics factors such as human leukocyte antigen HLA-B27 associates to AS susceptibility. We carried out a case-control study to determine whether the genetic polymorphisms of ORAI1 gene, a major component of store-operated calcium channels that involved the regulation of immune system, is a susceptibility factor to AS in a Taiwanese population. We enrolled 361 AS patients fulfilled the modified New York criteria and 379 controls from community. Five tagging single nucleotides polymorphisms (tSNPs) at ORAI1 were selected from the data of Han Chinese population in HapMap project. Clinical statuses of AS were assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Global Index (BAS-G). Our results indicated that subjects carrying the minor allele homozygote (CC) of the promoter SNP rs12313273 or TT homozygote of the SNP rs7135617 had an increased risk of HLA-B27 positive AS. The minor allele C of 3′UTR SNP rs712853 exerted a protective effect to HLA-B27 positive AS. Furthermore, the rs12313273/rs7135617 pairwise allele analysis found that C-G (OR 1.69, 95% CI 1.27, 2.25; p = 0.0003) and T-T (OR 1.75, 95% CI 1.36, 2.27; p<0.0001) haplotypes had a significantly association with the risk of HLA-B27-positive AS in comparison with the T-G carriers. This is the first study that indicate haplotypes of ORAI1 (rs12313273 and rs7135617) are associated with the risk of HLA-B27 positive AS.

A polymorphism of the ORAI1 gene is associated with the risk and recurrence of calcium nephrolithiasis

PURPOSE Store-operated calcium entry has been considered an important factor to regulate inflammatory reactions in nonexcitable cells. However, the effects of genetic polymorphisms of ORAI1, a main component of store-operated calcium channels, on nephrolithiasis and stone recurrence remain unclear. We investigated the association between calcium containing nephrolithiasis and genetic variants of ORAI1 gene in Taiwanese patients. MATERIALS AND METHODS A case-control study was performed in 136 patients with nephrolithiasis and 500 controls. Five tagging single nucleotide polymorphisms of ORAI1 were selected for genotyping. ORAI1 genotypes were determined by TaqMan® assay. Hardy-Weinberg equilibrium in cases and controls was assessed, and genetic effects were evaluated by the chi-square test and sliding window haplotype analysis. Subset analysis was done according to family history. RESULTS Two single nucleotide polymorphisms (rs12313273 and rs6486795) of the ORAI1 gene were associated with the risk of nephrolithiasis. The C allele carrier for rs12313273 was strongly related to recurrent stone forming in patients. On sliding window analysis the results of the 2 (rs12313273 and rs7135617) and the 3 (rs12313273, rs7135617 and rs6486795) single nucleotide polymorphism haplotypes had more significant effects on the risk of nephrolithiasis than the single nucleotide polymorphism rs12313273. CONCLUSIONS To our knowledge this is the first study identifying the novel polymorphisms of the ORAI1 gene, which may predispose to the risk of calcium nephrolithiasis and disease recurrence.

A Chinese herbal medicine, jia-wei-xiao-yao-san, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.

Jia-wei-xiao-yao-san (JWXYS) is a traditional Chinese herbal medicine that is widely used to treat neuropsychological disorders. Only a few of the hepatoprotective effects of JWXYS have been studied. The aim of this study was to investigate the hepatoprotective effects of JWXYS on dimethylnitrosamine- (DMN-) induced chronic hepatitis and hepatic fibrosis in rats and to clarify the mechanism through which JWXYS exerts these effects. After the rats were treated with DMN for 3 weeks, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were significantly elevated, whereas the albumin level decreased. Although DMN was continually administered, after the 3 doses of JWXYS were orally administered, the SGOT and SGPT levels significantly decreased and the albumin level was significantly elevated. In addition, JWXYS treatment prevented liver fibrosis induced by DMN. JWXYS exhibited superoxide-dismutase-like activity and dose-dependently inhibited DMN-induced lipid peroxidation and xanthine oxidase activity in the liver of rats. Our findings suggest that JWXYS exerts antifibrotic effects against DMN-induced chronic hepatic injury. The possible mechanism is at least partially attributable to the ability of JWXYS to inhibit reactive-oxygen-species-induced membrane lipid peroxidation.

Population-Based 5-Year Follow-Up Study in Taiwan of Dementia and Risk of Stroke

Background This study estimates the risk of stroke within 5 years of newly diagnosed dementia among elderly persons aged 65 and above. We examined the relationship between antipsychotic usage and development of stroke in patients with dementia. Methods We conducted a nationwide 5-year population-based study using data retrieved from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan. The study cohort comprised 2243 patients with dementia aged ≥65 years who had at least one inpatient service claim or at least 2 ambulatory care claims, whereas the comparison cohort consisted of 6714 randomly selected subjects (3 for every dementia patient) and were matched with the study group according to sex, age, and index year. We further classified dementia patients into 2 groups based on their history of antipsychotic usage. A total of 1450 patients were classified into the antipsychotic usage group and the remaining 793 patients were classified into the non-antipsychotic usage group. Cox proportional-hazards regressions were performed to compute the 5-year stroke-free survival rates after adjusting for potentially confounding factors. Results The dementia patients have a 2-fold greater risk of developing stroke within 5 years of diagnosis compared to non-dementia age- and sex-matched subjects, after adjusting for other risk factors (95% confidence interval (CI) = 2.58–3.08; P<.001). Antipsychotic usage among patients with dementia increases risk of stroke 1.17-fold compared to patients without antipsychotic treatment (95% CI = 1.01–1.40; P<.05). Conclusions Dementia may be an independent risk factor for stroke, and the use of antipsychotics may further increase the risk of stroke in dementia patients.

DC-SIGN (CD209) Promoter −336 A/G (rs4804803) Polymorphism Associated with Susceptibility of Kawasaki Disease

Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is the most effective therapy for KD to reduce the prevalence of coronary artery lesion (CAL) formation. Recently, the α2, 6 sialylated IgG was reported to interact with a lectin receptor, specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) in mice and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) in human, and to trigger an anti-inflammatory cascade. This study was conducted to investigate whether the polymorphism of DC-SIGN (CD209) promoter −336 A/G (rs4804803) is responsible for susceptibility and CAL formation in KD patients using Custom TaqMan SNP Genotyping Assays. A total of 521 subjects (278 KD patients and 243 controls) were investigated to identify an SNP of rs4804803, and they were studied and showed a significant association between the genotypes and allele frequency of rs4804803 in control subjects and KD patients (P = 0.004 under the dominant model). However, the promoter variant of DC-SIGN gene was not associated with the occurrence of IVIG resistance, CAL formation in KD. The G allele of DC-SIGN promoter −336 (rs4804803) is a risk allele in the development of KD.

Increased risk of benign prostate hyperplasia in sleep apnea patients: a nationwide population-based study.

Background Sleep apnea (SA) is a common sleep disorder characterized by chronic intermittent hypoxia (IH). Chronic IH induces systemic inflammatory processes, which can cause tissue damage and contribute to prostatic enlargement. The purpose of this study was to evaluate the association between benign prostate hyperplasia (BPH) and SA in a Taiwanese population. Methods The study population was identified from Taiwan’s National Health Insurance Research Database (NHIRD) and contained 202 SA patients and 1010 control patients. The study cohort consisted of men aged ≥30 years who were newly diagnosed with SA between January 1997 and December 2005. Each patient was monitored for 5 years from the index date for the development of BPH. A Cox regression analysis was used to calculate the hazard ratios (HRs) for BPH in the SA and control patients. Results During the 5-year follow-up, 18 SA patients (8.9%) and 32 non-SA control patients (3.2%) developed BPH. The adjusted HR for BPH was 2.35-fold higher in the patients with SA than in the control patients (95% confidence interval (CI) 1.28–4.29, P<.01). We further divided the SA patients into 4 age groups. After adjusting for potential confounding factors, the highest adjusted HR for BPH in the SA patients compared with the control patients was 5.59 (95% CI = 2.19–14.31, P<.001) in the patients aged between 51 and 65 years. Conclusion Our study results indicate that patients with SA are associated with increased longitudinal risk of BPH development, and that the effects of SA on BPH development are age-dependent.