We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese ...population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10(-7) (rs2709736) and 6.05 × 10(-6) (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10(-6)) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10(-5)), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10(-5) and P=1.48 × 10(-5), respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.
Summary
Recent studies found that hepatitis C virus (HCV) may invade the central nervous system, and both HCV and Parkinson's disease (PD) have in common the overexpression of inflammatory ...biomarkers. We analysed data from a community‐based integrated screening programme based on a total of 62 276 subjects. We used logistic regression models to investigate association between HCV infection and PD. The neurotoxicity of HCV was evaluated in the midbrain neuron–glia coculture system in rats. The cytokine/chemokine array was performed to measure the differences of amounts of cytokines released from midbrain in the presence and absence of HCV. The crude odds ratios (ORs) for having PD were 0.62 95% confidence interval (CI), 0.48–0.81 and 1.91 (95% CI, 1.48–2.47) for hepatitis B virus (HBV) and HCV. After controlling for potential confounders, the association between HCV and PD remained statistically significant (adjusted OR = 1.39; 95% CI, 1.07–1.80), but not significantly different between HBV and PD. The HCV induced 60% dopaminergic neuron death in the midbrain neuron–glia coculture system in rats, similar to that of 1‐methyl‐4‐phenylpyridinium (MPP+) but not caused by HBV. This link was further supported by the finding that HCV infection may release the inflammatory cytokines, which may play a role in the pathogenesis of PD. In conclusion, our study demonstrated a significantly positive epidemiological association between HCV infection and PD and corroborated the dopaminergic toxicity of HCV similar to that of MPP+.
Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic ...modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen-glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1β and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1β and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.
Asian women have a younger age at onset of breast cancer and a lower body mass index (BMI) than Western women. The link between obesity and risk of breast cancer in Asian women is still elusive. We ...aimed to investigate the effect of BMI on the risk of incident breast cancer in Taiwanese women.
A total of 1,393,985 women who had been cancer-free before recruitment and attended a nation-wide Taiwanese breast cancer-screening program between 1999 and 2009 were enrolled using a prospective cohort study. Obesity and other relevant variables (such as menopause status and other biochemical markers) were collected through in-person interviews, anthropometric measurements and blood samples at first screen. Incident breast cancers during follow-up were ascertained through the linkage of the cohort with the National Cancer Registry and the National Death Certification System.
A total of 6969 and 7039 incident breast cancer cases were identified among women enrolled before and after menopause, respectively. Compared with a BMI range of 18.5-23.9 kg m(-)(2), the incremental level of BMI in the enrolled women before menopause revealed a lack of statistically significant association with the risk of incident breast cancer (adjusted hazard ratio=0.94, 0.98, 1.02, 1.01 and 0.82 for BMI <18.5, 24-26.9, 27-29.9, 30-34.9 and ⩾35, respectively), but the incremental level of BMI in the enrolled women after menopause led to a statistically significant incremental increase in the risk of breast cancer (adjusted hazard ratio=0.78, 1.19, 1.31, 1.53 and 1.65 for BMI <18.5, 24-26.9, 27-29.9, 30-34.9 and ⩾35, respectively) after adjusting for other explanatory risk factors.
Obesity acts mainly as an influential promoter of the development of late-onset breast cancer after menopause in Taiwanese women.
Osteoporosis is a global disease burden for aging society. The role of quantitative ultrasound(QUS) in the prediction for osteoporosis in a dose-response manner is hardly addressed.
We aimed to show ...the dose-response of QUS measurement in the prediction for osteoporosis by a community-based study.
A prospective cohort study.
Participants were recruited between 2000 and 2004. Demographic data and heel QUS measurement were collected at baseline. Diagnosis of osteoporosis was ascertained by the follow-up of this cohort over time. In order to reduce the imbalance of baseline characteristics in the observational study, we applied propensity score by using proportional odds regression analysis to match the quintiles of QUS T-score.
A total of 44957 subjects composed of 17678 men (39.3%) and 27279 women (69.7%) were recruited. After adjustments for propensity score, an increase in one unit of QUB T-score led to 7% reduction in the risk for osteoporosis (adjusted odds ratioOR=0.93(95% CI: 0.89-0.96, P < 0.0001). Higher quintile of QUS T-score yielded a lower risk of osteoporosis with a gradient relationship (OR: 0.82 95%CI: 0.72-0.92; OR: 0.81 95%CI: 0.71-0.91; OR: 0.77 95%CI: 0.68-0.87 and OR: 0.76 95%CI: 0.67-0.86 from the second to highest quintile opposed to first quintile, P < 0.0001). The cumulative incidence of osteoporosis was higher in the lower quintile during follow-up(log-rank test, P < 0.001).
QUS is an independent predictor for osteoporosis in a dose-response manner using a large population-based cohort. Due to the lower cost and portability of QUS measurement, the pre-screening for osteoporosis by QUS can be considered in the area with limited resources can be a feasible and alternative method.
Periodontal disease and colorectal cancer have inflammatory processes in common. It is therefore worthwhile to investigate whether there is an association between periodontal probing depth and fecal ...hemoglobin concentration (FHbC), an indicator of colorectal neoplasms, in 40- to 44-year-old Taiwanese. We enrolled a total of 6,214 attendees aged 40 to 44 yr who were participating in a community-based integrated screening program and who received both periodontal and FHbC examinations between 2003 and 2008. A proportional odds logistic regression model was used to estimate the odds ratios of different FHbC levels in treating an increased level of community periodontal index (CPI) measuring periodontal probing depth as ordinary data from 0 to 4. Periodontal probing depth with the order of CPI was in parallel with an increase in the mean values of FHbC: 21.3 ± 156.3, 26.0 ± 167.7, 27.2 ± 151.1, and 39.5 ± 255.7 ng/mL for CPI 0, CPI 1, CPI 2, and CPI 3/4, respectively. The log-FHbC varied across the categories of CPI (p = .0078). After adjusting for age, sex, education level, smoking, alcohol intake, exercise, body mass index, and intake of meat and vegetables, subjects with positive fecal immunochemical test results (FHbC ≥ 100 ng/mL) had a 33% higher risk of deteriorating to severe CPI than did those within the normal range of fecal immunochemical test (FHbC < 100 ng/mL) (adjusted odds ratio = 1.33, 95% confidence interval: 1.03-1.73). A positive association was demonstrated between FHbC and periodontal probing depth assessed by CPI among 6,214 Taiwanese aged 40 to 44 yr who participated in a community-based integrated health screening program. These results could have significant implications for early identification of high-risk individuals, as those with deep periodontal pockets should be advised to undergo screening for colorectal cancer at a younger age than commonly recommended.
Background
It is of paramount importance to evaluate the impact of participation in organized mammography service screening independently from changes in breast cancer treatment. This can be done by ...measuring the incidence of fatal breast cancer, which is based on the date of diagnosis and not on the date of death.
Methods
Among 549,091 women, covering approximately 30% of the Swedish screening‐eligible population, the authors calculated the incidence rates of 2473 breast cancers that were fatal within 10 years after diagnosis and the incidence rates of 9737 advanced breast cancers. Data regarding each breast cancer diagnosis and the cause and date of death of each breast cancer case were gathered from national Swedish registries. Tumor characteristics were collected from regional cancer centers. Aggregated data concerning invitation and participation were provided by Sectra Medical Systems AB. Incidence rates were analyzed using Poisson regression.
Results
Women who participated in mammography screening had a statistically significant 41% reduction in their risk of dying of breast cancer within 10 years (relative risk, 0.59; 95% CI, 0.51‐0.68 P < .001) and a 25% reduction in the rate of advanced breast cancers (relative risk, 0.75; 95% CI, 0.66‐0.84 P < .001).
Conclusions
Substantial reductions in the incidence rate of breast cancers that were fatal within 10 years after diagnosis and in the advanced breast cancer rate were found in this contemporaneous comparison of women participating versus those not participating in screening. These benefits appeared to be independent of recent changes in treatment regimens.
Substantial and significant reductions in the incidence rates of fatal breast cancer and advanced breast cancer with 10 years of follow‐up are observed in this analysis of greater than one‐half million Swedish women participating and not participating in breast cancer screening. These comparisons are contemporaneous, and thus are not influenced by changes in therapeutic regimens.
Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, ...Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) ($P<10^{-7}$). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value=4.7× 10-24 and in 19 (20%) of 93 of healthy subjects 393.51 (23.23-6665.26); corrected P value=8.1× 10-18. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.
We aim to report the prevalence of irritable bowel syndrome (IBS) and elucidate the influence of IBS on the incidence of colorectal neoplasm through a community-screening-based, longitudinal ...follow-up study.
We enroled 39,384 community residents aged 40 years or older who had participated in a community-based colorectal cancer-screening programme with an immunochemical faecal occult test since 1999. We followed a cohort that was free of colorectal neoplasm (excluding colorectal neoplasm at baseline) to ascertain the incident colorectal neoplasm through each round of screening and used a nationwide cancer registry. Information on IBS was obtained by linking this screened cohort with population-based health insurance claim data. Other confounding factors were also collected via questionnaire or biochemical tests.
The overall period prevalence of IBS was 23%, increasing from 14.7% for subjects aged 40-49 years to 43.7% for those aged 70 years and more. After controlling for age, gender and family history of colorectal cancer, screenees who had been diagnosed as having IBS exhibited a significantly elevated level (21%; adjusted hazard ratio (HR)=1.21 (95% CI: 1.02-1.42)) of incident colorectal adenoma compared with those who had not been diagnosed with IBS. A similar finding was noted for invasive carcinoma; however, the size of the effect was of borderline statistical significance (adjusted HR=1.20 (95% CI: 0.94-1.53)).
IBS led to an increased risk for incident colorectal neoplasm.
Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this ...lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r(2)=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4(+) T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.
PDF
