Prediction of venous thromboembolism incidence in the general adult population using two published genetic risk scores

Introduction Most strategies for prevention of venous thromboembolism focus on preventing recurrent events. Yet, primary prevention might be possible through approaches targeting the whole population or high-risk patients. To inform possible prevention strategies, population-based information on the ability of genetic risk scores to identify risk of incident venous thromboembolism is needed. Materials and methods We used proportional hazards regression to relate two published genetic risk scores (273-variants versus 5-variants) with venous thromboembolism incidence in the Atherosclerosis Risk in Communities Study (ARIC) cohort (n = 11,292), aged 45–64 at baseline, drawn from 4 US communities. Results Over a median of 28 years, ARIC identified 788 incident venous thromboembolism events. Incidence rates rose more than two-fold across quartiles of the 273-variant genetic risk score: 1.7, 2.7, 3.4 and 4.0 per 1,000 person-years. For White participants, age, sex, and ancestry-adjusted hazard ratios (95% confidence intervals) across quartiles were strong [1 (reference), 1.30 (0.99,1.70), 1.85 (1.43,2.40), and 2.58 (2.04,3.28)] but weaker for Black participants [1, 1.05 (0.63,1.75), 1.37 (0.84,2.22), and 1.32 (0.80,2.20)]. The 5-variant genetic risk score showed a less steep gradient, with hazard ratios in Whites of 1, 1.17 (0.89,1.54), 1.48 (1.14,1.92), and 2.18 (1.71,2.79). Models including the 273-variant genetic risk score plus lifestyle and clinical factors had a c-statistic of 0.67. Conclusions In the general population, middle-aged adults in the highest quartile of either genetic risk score studied have approximately two-fold higher risk of an incident venous thromboembolism compared with the lowest quartile. The genetic risk scores show a weaker association with venous thromboembolism for Black people

Reasons for Differences in the Incidence of Venous Thromboembolism in Black Versus White Americans

Introduction: Venous thromboembolism incidence rates are 30%-100% higher in US blacks than whites. We examined the degree to which differences in the frequencies of socioeconomic, lifestyle, medical risk factors, and genetic variants explain the excess venous thromboembolism risk in blacks and whether some risk factors are more strongly associated with venous thromboembolism in blacks compared with whites. Methods: We measured venous thromboembolism risk factors in black and white participants of the Atherosclerosis Risk in Communities study in 1987-1989 and followed them prospectively through 2015 for venous thromboembolism incidence. Results: Over a mean of 22 years, we identified 332 venous thromboembolisms in blacks and 578 in whites, yielding 65% higher crude incidence rates per 1000 person-years in blacks. The age and sex-adjusted hazard ratio (95% confidence interval) of venous thromboembolism for blacks compared with whites was 2.04 (1.76, 2.37) for follow-up > 10 years and was attenuated to 1.14 (0.89, 1.46) when adjusted for baseline confounders or mediators of the race association, which tended to be more common in blacks. For example, adjustment for just baseline weight, family income, and concentration of plasma factor VIII reduced the regression coefficient for race by 75%. There were no significant (P < 0.05) 2-way multiplicative interactions of race with any risk factor, except with a 5-single nucleotide polymorphism (5-SNP) genetic risk score (a weaker venous thromboembolism risk factor in blacks) and with hospitalization for heart failure (a stronger venous thromboembolism risk factor in blacks). Conclusion: The higher incidence rate of venous thromboembolism in blacks than whites was mostly explained by blacks having higher frequencies of venous thromboembolism risk factors

Nucleic Acid-based Detection of Bacterial Pathogens Using Integrated Microfluidic Platform Systems

The advent of nucleic acid-based pathogen detection methods offers increased sensitivity and specificity over traditional microbiological techniques, driving the development of portable, integrated biosensors. The miniaturization and automation of integrated detection systems presents a significant advantage for rapid, portable field-based testing. In this review, we highlight current developments and directions in nucleic acid-based micro total analysis systems for the detection of bacterial pathogens. Recent progress in the miniaturization of microfluidic processing steps for cell capture, DNA extraction and purification, polymerase chain reaction, and product detection are detailed. Discussions include strategies and challenges for implementation of an integrated portable platform

Association of rs780094 in GCKR with Metabolic Traits and Incident Diabetes and Cardiovascular Disease: The ARIC Study

The minor T-allele of rs780094 in the glucokinase regulator gene (GCKR) associates with a number of metabolic traits including higher triglyceride levels and improved glycemic regulation in study populations of mostly European ancestry. Using data from the Atherosclerosis Risk in Communities (ARIC) Study, we sought to replicate these findings, examine them in a large population-based sample of African American study participants, and to investigate independent associations with other metabolic traits in order to determine if variation in GKCR contributes to their observed clustering. In addition, we examined the association of rs780094 with incident diabetes, coronary heart disease (CHD), and stroke over up mean follow-up times of 8, 15, and 15 years, respectively.Race-stratified analyses were conducted among 10,929 white and 3,960 black participants aged 45-64 at baseline assuming an additive genetic model and using linear and logistic regression and Cox proportional hazards models.Previous findings replicated among white participants in multivariable adjusted models: the T-allele of rs780094 was associated with lower fasting glucose (p = 10(-7)) and insulin levels (p = 10(-6)), lower insulin resistance (HOMA-IR, p = 10(-9)), less prevalent diabetes (p = 10(-6)), and higher CRP (p = 10(-8)), 2-h postprandial glucose (OGTT, p = 10(-6)), and triglyceride levels (p = 10(-31)). Moreover, the T-allele was independently associated with higher HDL cholesterol levels (p = 0.022), metabolic syndrome prevalence (p = 0.043), and lower beta-cell function measured as HOMA-B (p = 0.011). Among black participants, the T-allele was associated only with higher triglyceride levels (p = 0.004) and lower insulin levels (p = 0.002) and HOMA-IR (p = 0.013). Prospectively, the T-allele was associated with reduced incidence of diabetes (p = 10(-4)) among white participants, but not with incidence of CHD or stroke.Our findings indicate rs780094 has independent associations with multiple metabolic traits as well as incident diabetes, but not incident CHD or stroke. The magnitude of association between the SNP and most traits was of lower magnitude among African American compared to white participants

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention