Causal Associations Between Serum Bilirubin Levels and Decreased Stroke Risk: A Two-Sample Mendelian Randomization Study

OBJECTIVE: A number of epidemiological studies have reported that decreased serum bilirubin, an endogenous antioxidant, is associated with cardiovascular disease. However, previous Mendelian randomization analyses conducted using a single sample have shown no evidence of association. Approach and Results: A 2-sample summary Mendelian randomization study was performed by obtaining exposure and outcome data from separate nonoverlapping samples. We utilized data from the KoGES (Korean Genome and Epidemiology Study; n=25 406) and KCPS-II (Korean Cancer Prevention Study-II; n=14 541) biobank for serum bilirubin and stroke, respectively. Using KoGES, a total of 1784 single nucleotide polymorphisms associated with serum bilirubin levels were discovered using a genome-wide significance threshold (P<5×10-8), of which 10 single nucleotide polymorphisms were identified as independent (R2<0.005) and adopted as genetic instruments. From KCPS-II, total and ischemic stroke cases were identified (n=1489 and n=686), with 12 366 acting as controls. Various 2-sample summary Mendelian randomization methods were employed, with Mendelian randomization estimates showing an inverse causal association between serum bilirubin levels and total stroke risk (odds ratio, 0.481 [95% CI, 0.234-0.988]; P=0.046). This association increased in magnitude when restricting the analysis to ischemic stroke cases (odds ratio, 0.302 [95% CI, 0.105-0.868]; P=0.026). CONCLUSIONS: Our findings provide evidence of significant causal relationship between high levels of bilirubin and decreased stroke risk in Korean population in agreement with observational approaches. This highlights the potential for bilirubin to serve as a therapeutic target for oxidative stress-related diseases such as stroke and suggests that previous findings were not a consequence of unmeasured confounding.ope

Bilirubin and risk of ischemic heart disease in Korea: a two-sample Mendelian randomization study

OBJECTIVES: Bilirubin is an endogenous antioxidant that protects cells against oxidative stress. Increased plasma levels of bilirubin have been associated with a reduced risk of ischemic heart disease (IHD) in previous studies. Nonetheless, whether those associations reflect a true protective effect of bilirubin on IHD, rather than confounding or reverse causation, remains unknown. Therefore, we applied two-sample Mendelian randomization to evaluate the causal association between bilirubin levels and IHD risk in a Korean population. METHODS: A total of 5 genetic variants-TRPM8 (rs10490012), USP40 (rs12993249), ATG16L1 (rs2119503), SLCO1B1 (rs4149014), and SLCO1B3 (rs73233620)-were selected as genetic instruments for serum bilirubin levels using a communitybased cohort, the Korean Genome and Epidemiology Study, comprising 33,598 subjects. We then evaluated their impact on IHD using the Korean Cancer Prevention Study-II cohort. RESULTS: Among the 5 instrumental variables that showed significant associations with serum bilirubin levels, rs12993249 (USP40) showed the most significant association (p<2.36×10-105). However, we found no significant association between serum bilirubin levels and IHD. Sensitivity analyses demonstrated a consistent association, suggesting that our observations were robust. CONCLUSIONS: Using two-sample Mendelian randomization, we found no association between serum bilirubin levels and IHD. Further studies that confirm the observed interactions among other ethnicities are warranted.ope

The associations between immunity-related genes and breast cancer prognosis in Korean women

We investigated the role of common genetic variation in immune-related genes on breast cancer disease-free survival (DFS) in Korean women. 107 breast cancer patients of the Seoul Breast Cancer Study (SEBCS) were selected for this study. A total of 2,432 tag single nucleotide polymorphisms (SNPs) in 283 immune-related genes were genotyped with the GoldenGate Oligonucleotide pool assay (OPA). A multivariate Cox-proportional hazard model and polygenic risk score model were used to estimate the effects of SNPs on breast cancer prognosis. Harrell's C index was calculated to estimate the predictive accuracy of polygenic risk score model. Subsequently, an extended gene set enrichment analysis (GSEA-SNP) was conducted to approximate the biological pathway. In addition, to confirm our results with current evidence, previous studies were systematically reviewed. Sixty-two SNPs were statistically significant at p-value less than 0.05. The most significant SNPs were rs1952438 in SOCS4 gene (hazard ratio (HR) = 11.99, 95% CI = 3.62-39.72, P = 4.84E-05), rs2289278 in TSLP gene (HR = 4.25, 95% CI = 2.10-8.62, P = 5.99E-05) and rs2074724 in HGF gene (HR = 4.63, 95% CI = 2.18-9.87, P = 7.04E-05). In the polygenic risk score model, the HR of women in the 3rd tertile was 6.78 (95% CI = 1.48-31.06) compared to patients in the 1st tertile of polygenic risk score. Harrell's C index was 0.813 with total patients and 0.924 in 4-fold cross validation. In the pathway analysis, 18 pathways were significantly associated with breast cancer prognosis (P<0.1). The IL-6R, IL-8, IL-10RB, IL-12A, and IL-12B was associated with the prognosis of cancer in data of both our study and a previous study. Therefore, our results suggest that genetic polymorphisms in immune-related genes have relevance to breast cancer prognosis among Korean women.ope

Prediction of breast cancer survival using clinical and genetic markers by tumor subtypes

PURPOSE: To identify the genetic variants associated with breast cancer survival, a genome-wide association study (GWAS) was conducted of Korean breast cancer patients. METHODS: From the Seoul Breast Cancer Study (SEBCS), 3,226 patients with breast cancer (1,732 in the discovery and 1,494 in the replication set) were included in a two-stage GWAS on disease-free survival (DFS) by tumor subtypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). The associations of the re-classified combined prognostic markers through recursive partitioning analysis (RPA) of DFS for breast cancer were assessed with the Cox proportional hazard model. The prognostic predictive values of the clinical and genetic models were evaluated by Harrell's C. RESULTS: In the two-stage GWAS stratified by tumor subtypes, rs166870 and rs10825036 were consistently associated with DFS in the HR+ HER2- and HR- HER2- breast cancer subtypes, respectively (Prs166870 = 2.88 × 10(-7) and Prs10825036 = 3.54 × 10(-7) in the combined set). When patients were classified by the RPA in each subtype, genetic factors contributed significantly to differentiating the high risk group associated with DFS inbreast cancer, specifically the HR+ HER2- (P discovery=1.18 × 10(-8) and P replication = 2.08 × 10(-5)) and HR- HRE2- subtypes (P discovery = 2.35 × 10(-4) and P replication = 2.60 × 10(-2)). The inclusion of the SNPs tended to improve the performance of the prognostic models consisting of age, TNM stage and tumor subtypes based on ER, PR, and HER2 status. CONCLUSION: Combined prognostic markers that include clinical and genetic factors by tumor subtypes could improve the prediction of survival in breast cancer.ope

조선시대 성 통제에 대한 보고

[서평] 이숙인(2014), 정절의 역사 , 푸른역사, 424쪽.이 책은 조선시대 국가적으로 이루어졌던 여성에 대한 성(性)통제의 역사를 밝힌 책이다. 저자는 경국대전등의 법전, 내훈, 여사서등의 여성교육서, 실록과 심리록등의 판결기록 등 다양한 자료를 통해서 성 통제의 역사에 접근하고 있다. 저자가 인용하는 조선시대 성 담론과 성 스캔들의 이야깃거리는 여성 성 통제의 역사를 다채롭게 펼쳐 보인다

A Study on the ICCP Control and Monitoring System for Ship

This thesis is about the Impressed Current Cathodic Protection (ICCP) control and monitoring system, which brings protection against the corrosion of the ship's hull in the sea. The ship's hull is composed of iron which can be highly corroded, and therefore the corrosion brings about great physical and financial damages to the ship. Because of this, the protection against the corrosion of iron is a necessity. Since there is no one perfect way to protect against corrosion and rapid degradation, an anti-corrosive protection method, such as coating, has to run simultaneously with an electrical anti-corrosive device. The ICCP system which I will be discussing is one such method, and has several advantages. First, the life of the anode is long because the ICCP system uses an insoluble anode. Second, it can get enough protective current over a large area for protection. Iron can be separated into three regions of corrosion, immunity and passivity. Without any external force, iron's corrosion potential under natural conditions is within a corrosion range, so such iron becomes corroded. On the other hand, protection of the vessel's hull can be made because iron's corrosion potential can be transferred to an immunity range when the ICCP system compels a protective current to be sent to the ship's hull. Iron's corrosion potential is -600mV with standard hydrogen electrode (SHE), and its protective potential is between -800mV and -900mV. The ICCP system is composed of a power supply, anode, reference electrode and controller. AC sources from the ship's generator are converted to DC sources in terms of power supply, and a protective current is sent to ship's hull though anode. A Zinc electrode is used for a reference electrode. Zinc's potential is -1000mV with SHE. Differential potential is detected by a sensor between the ship's hull and the reference electrode, and its value must be controlled to maintain between +100mV and +200mV. Then ship's hull can always be protected. When the system is abnormal, it is designed to sound the alarm. The controller operates to increase the protective current at the anode if the value of the detected potential is lower than that of the setting potential, but it operates to decrease it if the former is higher than the latter. The controller fully senses whether or not the detected potential is within a range of protection and then it is automatically controlled to increase or decrease the amount of protective current to be sent to the anode. The monitoring system with RS 232/485 communication is also studied in order to check the normal state of the system at a long distance, because an operator does not always watch over this system and thus the system cannot operate well because of his or her negligent management. Since the ship always moves in the sea, an experiment of characteristics of the ICCP system is conducted by introducing various corrosional environmental factors such as velocity and pollution. First, the amount of the requisite protective current is not consistent enough to protect against corrosion of the ship's hull because the velocity is different at anchor and on the voyage. That is, the faster the velocity, the more the requisite protective current is increased. Second, the amount of the requisite protective current is also inconsistent because pollution levels are different when sailing along the coast compared to sailing out at sea. That is, the heavier the pollution, the more the requisite protective current is increased. These results must be referred to when the ICCP system is set up. In short, the ICCP is a multi-system for use on ships and on land structures because it includes a safety device. Even over a long distance, the system's conditions can be watched through a monitoring system with communication. The system can be controlled to protect against corrosion of the ship's hull in different corrosional environments. I suggest that this system can accomodate a ship's automation and will be very useful.제 1 장 서론 1 1.1 연구배경 1 1.2 연구목적 3 1.3 논문구성 5 제 2 장 ICCP 6 2.1 개요 6 2.2 방식 및 방식 9 2.3 선박의 운용 특성 17 제 3 장 제어시스템 설계 20 3.1 개요 20 3.2 소프트웨어 설계 22 3.2.1 알고리즘 23 3.2.2 프로그램 30 3.3 하드웨어 설계 36 3.3.1 구성 37 3.3.2 세미컨버터형 정류기 39 3.3.3 구동회로 42 3.3.4 모니터링 회로와 통신 회로 52 3.3.5 전원 회로 와 입출력 회로 57 제 4 장 실험 및 결과 63 4.1 실험장치 63 4.2 특성 실험 69 4.3 운용 실험(선박의 운용 특성에 따른 실험) 78 제 5 장 결론 80 참고 문헌 8