Precision Medicine and Cardiovascular Health: Insights from Mendelian Randomization Analyses

Cardiovascular disease (CVD) is considered a primary driver of global mortality and is estimated to be responsible for approximately 17.9 million deaths annually. Consequently, a substantial body of research related to CVD has developed, with an emphasis on identifying strategies for the prevention and effective treatment of CVD. In this review, we critically examine the existing CVD literature, and specifically highlight the contribution of Mendelian randomization analyses in CVD research. Throughout this review, we assess the extent to which research findings agree across a range of studies of differing design within a triangulation framework. If differing study designs are subject to non-overlapping sources of bias, consistent findings limit the extent to which results are merely an artefact of study design. Consequently, broad agreement across differing studies can be viewed as providing more robust causal evidence in contrast to limiting the scope of the review to a single specific study design. Utilising the triangulation approach, we highlight emerging patterns in research findings, and explore the potential of identified risk factors as targets for precision medicine and novel interventions.ope

혈청지질 농도와 우울증과의 관련성 연구

Objective : Low cholesterol is associated with depression among western countries. The objective of this study was to examine the relationship between cholesterol and depression in Korean population with low levels of serum cholesterol. Methods : The data of about 740,000 individuals, aged 30-64 years at entry in the Korean Cancer Prevention Study, were used. Total cholesterol levels were measured in 1992. Depression was measured using the modified DSM-IV (Diagnostic Criteria of Major Depressive Episode in Diagnostic and Statistical Manual of Mental Disorders-IV) scale. Total cholesterol was classified into four groups (quartile). Odds Ratios of low level of cholesterol were evaluated using multi-variable logistic models. Results : The prevalence of major depression was 7.7% in men and 10.4% in women. After adjustment for various confounding variables, an inverse association was detected between cholesterol levels and depression intensity among men and women. The odds ratio (95% confidence interval) of the lowest quartile of cholesterol was 1.16 (1.13-1.20) on major depression compared with the highest quartile of cholesterol in men. The corresponding odds ratio among women was 1.09 (1.04-1.15). The strongest association among 9 items of depression was found at "decreased appetite and lost weight" in both men (OR=1.68) and women (OR=1.43). Conclusions : Low cholesterol is associated with major depression in men and women. Further studies are necessary to evaluate the cross-validation, to explore the biological mechanism, and to identify the clinical implication.ope

Genome-wide association meta-analysis identifies novel variants associated with fasting plasma glucose in East Asians

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation.ope

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

Atherosclerotic cardiovascular disease prediction model and prescribing rates of statins : the Korean heart study

보건대학원/박사Background and Aims The aims of the study were to evaluate the performance of the American College of Cardiology/American Heart Association (ACC/AHA) 2013 Pooled Cohort Equations in the Korean Heart Study (KHS) population, to develop a Korean Risk Prediction Model (KRPM) for atherosclerotic cardiovascular disease (ASCVD) events, and to evaluate the relation between 10-year ASCVD risk score from two different ASCVD prediction equations and actual statin prescriptions in the last 10 years (2004-2013) in Korean general population. Methods The KHS cohort included 200,010 Korean adults aged 40-79 years who were free from ASCVD at baseline. Discrimination and calibration of the ACC/AHA 2013 Pooled Cohort Equations in predicting 10-year ASCVD risk in the KHS cohort were evaluated. Recalibration of the ACC/AHA Equations was done using coefficients from the pooled cohorts'' Cox model but mean values of risk factors and ASCVD incidence rates from the KHS cohort. The KRPM was derived using coefficients, mean risk factor values, and mean incidences from the KHS cohort. Per equations, we also calculated the prescribing rates of statins using cumulative incidence. Results In the discriminatory analysis, the ACC/AHA Equations for either White or African-American (AA) moderately distinguished cases from non-cases in the KHS cohort, and were similar to the KRPM: For men, the area under the receiver operating characteristic curve (AUROCs) were 0.727 (White model), 0.725 (AA model), and 0.741 (Korean model); for women, the AUROCs were 0.738, 0.739, and 0.745, respectively. Absolute 10-year ASCVD risk for men in the KHS cohort was overestimated by 56.5% in the White model and 74.1% in the AA model, while the risk for women was underestimated by 27.9% in the White model and overestimated by 29.1% in the AA model. Recalibration of the ACC/AHA Equations did not affect discriminatory ability but improved calibration substantially, especially in men in the White model. Of the three ASCVD risk prediction models, the KRPM showed the best calibration, with the lowest Hosmer-Lemeshow X2 for both men and women when used in a validation subsample. During the follow-up period, an overall prescribing rate of statins in women was 33.5% greater than that of men, 26.3%. Conclusions The ACC/AHA Equations should not be directly applied for ASCVD risk prediction in a Korean population. The KRPM showed best predictive ability for ASCVD risk. Therefore, utilization of the prediction risk score in deciding on preventive statin therapy is suggested for Korean population.ope

Stratifying the early radiologic trajectory in dyspneic patients with COVID-19 pneumonia

Objective: This study aimed to stratify the early pneumonia trajectory on chest radiographs and compare patient characteristics in dyspneic patients with coronavirus disease 2019 (COVID-19). Materials and methods: We retrospectively included 139 COVID-19 patients with dyspnea (87 men, 62.7±16.3 years) and serial chest radiographs from January to September 2020. Radiographic pneumonia extent was quantified as a percentage using a previously-developed deep learning algorithm. A group-based trajectory model was used to categorize the pneumonia trajectory after symptom onset during hospitalization. Clinical findings, and outcomes were compared, and Cox regression was performed for survival analysis. Results: Radiographic pneumonia trajectories were categorized into four groups. Group 1 (n = 83, 59.7%) had negligible pneumonia, and group 2 (n = 29, 20.9%) had mild pneumonia. Group 3 (n = 13, 9.4%) and group 4 (n = 14, 10.1%) showed similar considerable pneumonia extents at baseline, but group 3 had decreasing pneumonia extent at 1-2 weeks, while group 4 had increasing pneumonia extent. Intensive care unit admission and mortality were significantly more frequent in groups 3 and 4 than in groups 1 and 2 (P < .05). Groups 3 and 4 shared similar clinical and laboratory findings, but thrombocytopenia (<150×103/μL) was exclusively observed in group 4 (P = .016). When compared to groups 1 and 2, group 4 (hazard ratio, 63.3; 95% confidence interval, 7.9-504.9) had a two-fold higher risk for mortality than group 3 (hazard ratio, 31.2; 95% confidence interval, 3.5-280.2), and this elevated risk was maintained after adjusting confounders. Conclusion: Monitoring the early radiologic trajectory beyond baseline further prognosticated at-risk COVID-19 patients, who potentially had thrombo-inflammatory responses.ope

Smoking and atherosclerotic cardiovascular disease risk in young men: the Korean Life Course Health Study

OBJECTIVE: To examine the effect of smoking on risk of atherosclerotic cardiovascular disease (ASCVD) in Korean young men and to examine whether serum total cholesterol levels could modify the effect of smoking on ASCVD. DESIGN: A prospective cohort study within a national insurance system. SETTING: Health screenings provided by national insurance in 1992 and 1994. PARTICIPANTS: A total of 118 531 young men between 20 and 29 years of age and were followed up for an average of 23 years. OUTCOME MEASURE: To assess the independent effects of smoking on the risk of ischaemic heart disease (IHD), stroke and ASCVD, Cox proportional hazards regression models were used, controlling for age, hypertension, diabetes, hypercholesterolaemia and alcohol drinking. RESULTS: The total number of current smokers was 78 455 (66.2%), and 94 113 (79.7%) of the sample recorded a total cholesterol level <200 mg/dL measured at baseline. Between 1993 and 2015, 2786 cases of IHD (53/100 000 person year), 2368 cases of stroke (45.4/100 000 person year) and 6368 ASCVD (122.7/100 000 person year) occurred. The risk of IHD, stroke and total ASCVD events was found to increase for current smokers, with a HR with 95% CI of 1.5 (95% CI 1.3 to 1.6), 1.4 (95% CI 1.2 to 1.6) and 1.4 (95% CI 1.3 to 1.5), respectively. Furthermore, the risks above were also found throughout the range of serum levels of cholesterol. CONCLUSIONS: Smoking among Korean young adult men was independently associated with increased risk of IHD, stroke and ASCVD. The concentration of cholesterol in Korean men did not modify the effect of smoking on ASCVD.ope