Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk ...factors in the primary prevention of CVD.
Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age SD: 56.0 8.0 years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703-0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009-0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40-75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation.
Our results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale.
Abstract Objective Mendelian randomization is a popular technique for assessing and estimating the causal effects of risk factors. If genetic variants which are instrumental variables for a risk ...factor are shown to be additionally associated with a disease outcome, then the risk factor is a cause of the disease. However, in many cases, the instrumental variable assumptions are not plausible, or are in doubt. In this paper, we provide a theoretical classification of scenarios in which a causal conclusion is justified or not justified, and discuss the interpretation of causal effect estimates. Results A list of guidelines based on the ‘Bradford Hill criteria’ for judging the plausibility of a causal finding from an applied Mendelian randomization study is provided. We also give a framework for performing and interpreting investigations performed in the style of Mendelian randomization, but where the choice of genetic variants is statistically, rather than biologically motivated. Such analyses should not be assigned the same evidential weight as a Mendelian randomization investigation. Conclusion We discuss the role of such investigations (in the style of Mendelian randomization), and what they add to our understanding of potential causal mechanisms. If the genetic variants are selected solely according to statistical criteria, and the biological roles of genetic variants are not investigated, this may be little more than what can be learned from a well-designed classical observational study.
Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the ...associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta-analysis of prospective studies.
Interleukin-6 (IL-6), IL-18, matrix metalloproteinase-9 (MMP-9), soluble CD40 ligand (sCD40L), and tumour necrosis factor-α (TNF-α) were measured at baseline in a case-cohort study of 1514 participants and 833 incident CHD events within population-based prospective cohorts at the Danish Research Centre for Prevention and Health. Age- and sex-adjusted hazard ratios (HRs) for CHD per 1-SD higher log-transformed baseline levels were: 1.37 (95% CI: 1.21-1.54) for IL-6, 1.26 (1.11-1.44) for IL-18, 1.30 (1.16-1.46) for MMP-9, 1.01 (0.89-1.15) for sCD40L, and 1.13 (1.01-1.27) for TNF-α. Multivariable adjustment for conventional vascular risk factors attenuated the HRs to: 1.26 (1.08-1.46) for IL-6, 1.12 (0.95-1.31) for IL-18, 1.21 (1.05-1.39) for MMP-9, 0.93 (0.78-1.11) for sCD40L, and 1.14 (1.00-1.31) for TNF-α. In meta-analysis of up to 29 population-based prospective studies, adjusted relative risks for non-fatal MI or CHD death per 1-SD higher levels were: 1.25 (1.19-1.32) for IL-6; 1.13 (1.05-1.20) for IL-18; 1.07 (0.97-1.19) for MMP-9; 1.07 (0.95-1.21) for sCD40L; and 1.17 (1.09-1.25) for TNF-α.
Several different pro-inflammatory cytokines are each associated with CHD risk independent of conventional risk factors and in an approximately log-linear manner. The findings lend support to the inflammation hypothesis in vascular disease, but further studies are needed to assess causality.
Guidelines advocate changes in fatty acid consumption to promote cardiovascular health.
To summarize evidence about associations between fatty acids and coronary disease.
MEDLINE, Science Citation ...Index, and Cochrane Central Register of Controlled Trials through July 2013.
Prospective, observational studies and randomized, controlled trials.
Investigators extracted data about study characteristics and assessed study biases.
There were 32 observational studies (530,525 participants) of fatty acids from dietary intake; 17 observational studies (25,721 participants) of fatty acid biomarkers; and 27 randomized, controlled trials (103,052 participants) of fatty acid supplementation. In observational studies, relative risks for coronary disease were 1.02 (95% CI, 0.97 to 1.07) for saturated, 0.99 (CI, 0.89 to 1.09) for monounsaturated, 0.93 (CI, 0.84 to 1.02) for long-chain ω-3 polyunsaturated, 1.01 (CI, 0.96 to 1.07) for ω-6 polyunsaturated, and 1.16 (CI, 1.06 to 1.27) for trans fatty acids when the top and bottom thirds of baseline dietary fatty acid intake were compared. Corresponding estimates for circulating fatty acids were 1.06 (CI, 0.86 to 1.30), 1.06 (CI, 0.97 to 1.17), 0.84 (CI, 0.63 to 1.11), 0.94 (CI, 0.84 to 1.06), and 1.05 (CI, 0.76 to 1.44), respectively. There was heterogeneity of the associations among individual circulating fatty acids and coronary disease. In randomized, controlled trials, relative risks for coronary disease were 0.97 (CI, 0.69 to 1.36) for α-linolenic, 0.94 (CI, 0.86 to 1.03) for long-chain ω-3 polyunsaturated, and 0.89 (CI, 0.71 to 1.12) for ω-6 polyunsaturated fatty acid supplementations.
Potential biases from preferential publication and selective reporting.
Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats.
British Heart Foundation, Medical Research Council, Cambridge National Institute for Health Research Biomedical Research Centre, and Gates Cambridge.
Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated ...comprehensively, because available studies have involved limited genomic scope and limited sample sizes.
This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention.
Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank.
The hazard ratio (HR) for CAD was 1.71 (95% confidence interval CI: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age.
The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.
Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of ...cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels.
To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB.
Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017.
Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.
Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins.
A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 95% CI, 0.741-0.802, P = 3.9 × 10-38 and OR, 0.773 95% CI, 0.747-0.801, P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 95% CI, 0.965-1.065, P = .19; LDL-C: OR, 1.010 95% CI, 0.967-1.055, P = .19; ApoB: OR, 0.761 95% CI, 0.723-0.798, P = 7.51 × 10-20).
Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma ...protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.
Inflammation, which is directly regulated by interleukin-6 (IL-6) signaling, is implicated in the etiology of several chronic diseases. Although a common, non-synonymous variant in the IL-6 receptor ...gene (IL6R Asp358Ala; rs2228145 A>C) is associated with the risk of several common diseases, with the 358Ala allele conferring protection from coronary heart disease (CHD), rheumatoid arthritis (RA), atrial fibrillation (AF), abdominal aortic aneurysm (AAA), and increased susceptibility to asthma, the variant's effect on IL-6 signaling is not known. Here we provide evidence for the association of this non-synonymous variant with the risk of type 1 diabetes (T1D) in two independent populations and confirm that rs2228145 is the major determinant of the concentration of circulating soluble IL-6R (sIL-6R) levels (34.6% increase in sIL-6R per copy of the minor allele 358Ala; rs2228145 C). To further investigate the molecular mechanism of this variant, we analyzed expression of IL-6R in peripheral blood mononuclear cells (PBMCs) in 128 volunteers from the Cambridge BioResource. We demonstrate that, although 358Ala increases transcription of the soluble IL6R isoform (P = 8.3×10⁻²²) and not the membrane-bound isoform, 358Ala reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele; P≤5.6×10⁻²²). Importantly, reduced expression of membrane-bound IL-6R resulted in impaired IL-6 responsiveness, as measured by decreased phosphorylation of the transcription factors STAT3 and STAT1 following stimulation with IL-6 (P≤5.2×10⁻⁷). Our findings elucidate the regulation of IL-6 signaling by IL-6R, which is causally relevant to several complex diseases, identify mechanisms for new approaches to target the IL-6/IL-6R axis, and anticipate differences in treatment response to IL-6 therapies based on this common IL6R variant.
Abstract
Summary
flashfm-ivis provides a suite of interactive visualization plots to view potential causal genetic variants that underlie associations that are shared or distinct between multiple ...quantitative traits and compares results between single- and multi-trait fine-mapping. Unique features include network diagrams that show joint effects between variants for each trait and regional association plots that integrate fine-mapping results, all with user-controlled zoom features for an interactive exploration of potential causal variants across traits.
Availability and implementation
flashfm-ivis is an open-source software under the MIT license. It is available as an interactive web-based tool (http://shiny.mrc-bsu.cam.ac.uk/apps/flashfm-ivis/) and as an R package. Code and documentation are available at https://github.com/fz-cambridge/flashfm-ivis and https://zenodo.org/record/6376244#.YjnarC-l2X0. Additional features can be downloaded as standalone R libraries to encourage reuse.
Supplementary information
Supplementary information are available at Bioinformatics online.
Genomic atlas of the human plasma proteome Sun, Benjamin B; Maranville, Joseph C; Peters, James E ...
Nature (London),
06/2018, Letnik:
558, Številka:
7708
Journal Article
Recenzirano
Odprti dostop
Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels ...are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.
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