RESUMO
BACKGROUND: Accurate risk stratification is vital for primary prevention of cardiovascular disease (CVD). However, traditional tools such as the Framingham Risk Score (FRS) may underperform within the diverse intermediate-risk group, which includes individuals requiring distinct management strategies. OBJECTIVES: This study aimed to develop a lipidomic-enhanced risk score (LRS), specifically targeting risk prediction and reclassification within the intermediate group, benchmarked against the FRS. METHODS: The LRS was developed via a machine learning workflow using ridge regression on the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab; n = 10,339). It was externally validated with the Busselton Health Study (n = 4,492), and its predictive utility for coronary artery calcium scoring (CACS)-based outcomes was independently validated in the BioHEART cohort (n = 994). RESULTS: LRS significantly improved discrimination metrics for the intermediate-risk group in both AusDiab and Busselton Health Study cohorts (all P < 0.001), increasing the area under the curve for CVD events by 0.114 (95% CI: 0.1123-0.1157) and 0.077 (95% CI: 0.0755-0.0785), with a net reclassification improvement of 0.36 (95% CI: 0.21-0.51) and 0.33 (95% CI: 0.15-0.49), respectively. For CACS-based outcomes in BioHEART, LRS achieved a significant area under the curve improvement of 0.02 over the FRS (0.76 vs 0.74; P < 1.0 × 10-5). A simplified, clinically applicable version of LRS was also created that had comparable performance to the original LRS. CONCLUSIONS: LRS, augmenting the FRS, presents potential to improve intermediate-risk stratification and to predict atherosclerotic markers using a simple blood test, suitable for clinical application. This could facilitate the triage of individuals for noninvasive imaging such as CACS, fostering precision medicine in CVD prevention and management.
Assuntos
Doenças Cardiovasculares , Prevenção Primária , Humanos , Prevenção Primária/métodos , Medição de Risco/métodos , Feminino , Doenças Cardiovasculares/prevenção & controle , Pessoa de Meia-Idade , Masculino , Lipidômica/métodos , Idoso , Fatores de Risco de Doenças Cardíacas , Austrália/epidemiologia , Aprendizado de Máquina , AdultoRESUMO
We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in â¼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
Assuntos
Doença da Artéria Coronariana , Doença da Artéria Coronariana/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Homeostase , Humanos , Lipidômica , Lipídeos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: The traditional primary prevention paradigm for coronary artery disease (CAD) centers on population-based algorithms to classify individual risk. However, this approach often misclassifies individuals and leaves many in the 'intermediate' category, for whom there is no clear preferred prevention strategy. Coronary artery calcium (CAC) and polygenic risk scoring (PRS) are 2 contemporary tools for risk prediction to enhance the impact of effective management. AIMS: To determine how these CAC and PRS impact adherence to pharmacotherapy and lifestyle measures in asymptomatic individuals with subclinical atherosclerosis. METHODS: The CAPAR-CAD study is a multicenter, open, randomized controlled trial in Victoria, Australia. Participants are self-selected individuals aged 40 to 70 years with no prior history of cardiovascular disease (CVD), intermediate 10-year risk for CAD as determined by the pooled cohort equation (PCE), and CAC scores >0. All participants will have a health assessment, a full CT coronary angiogram (CTCA), and PRS calculation. They will then be randomized to receive their risk presented either as PCE and CAC, or PCE and PRS. The intervention includes e-Health coaching focused on risk factor management, health education and pharmacotherapy, and follow-up to augment adherence to a statin medication. The primary endpoint is a change in low-density lipoprotein cholesterol (LDL-C) from baseline to 12 months. The secondary endpoint is between-group differences in behavior modification and adherence to statin pharmacotherapy. RESULTS: As of July 31, 2021, we have screened 1,903 individuals. We present the results of the 574 participants deemed eligible after baseline assessment.
Assuntos
Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Cálcio , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/genética , Vasos Coronários , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Medição de Risco , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
Background Epidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid-derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin-angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti-inflammatory eicosanoids are linked with BP. Methods and Results We studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography-mass spectrometry, we profiled 545 distinct high-quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP (PAssuntos
Pressão Sanguínea
, Eicosanoides/sangue
, Adulto
, Idoso
, Pressão Sanguínea/fisiologia
, Eicosanoides/fisiologia
, Feminino
, Finlândia/epidemiologia
, Cromatografia Gasosa-Espectrometria de Massas
, Humanos
, Hipertensão/sangue
, Hipertensão/fisiopatologia
, Modelos Lineares
, Estudos Longitudinais
, Masculino
, Pessoa de Meia-Idade
, Oxilipinas/sangue
, Estados Unidos/epidemiologia
RESUMO
Phenotypic sex differences in coronary artery disease (CAD) and its risk factors have been apparent for many decades in basic and clinical research; however, whether these are also present at the gene level and thus influence genome-wide association and genetic risk prediction studies has often been ignored. From fundamental and medical standpoints, this is critically important to assess in order to fully understand the underlying genetic architecture that predisposes to CAD and better predict disease outcomes based on the interaction between genes, sex effects, and environment. In this chapter we aimed to (1) integrate the history and latest research from genome-wide association studies for CAD and clinical and genetic risk scores for prediction of CAD, (2) highlight sex-specific differences in these areas of research, and (3) discuss reasons why sex differences have often not been considered and, where present, why sex differences exist at genetic and phenotypic levels and how important they are for consideration in future research. While we find interesting examples of sex differences in effects of genetic variants on CAD, genome-wide association and genetic risk studies have typically not tested for sex-specific effects despite mounting evidence from diverse fields that these are likely very important to consider at both the genetic and phenotypic levels. In-depth testing for sex effects in large-scale genome-wide association studies that include autosomal and often excluded sex chromosomes alongside parallel improvements in resolution of sex-specific differences for risk factors and disease outcomes for CAD has the potential to substantially improve clinical and genetic risk prediction studies. Developing sex-tailored genetic risk scores as has been done recently for other disorders might be also warranted for CAD. In the era of precision medicine, this level of accuracy is essential for such a common and costly disease.
Assuntos
Doença da Artéria Coronariana/genética , Técnicas de Apoio para a Decisão , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Disparidades nos Níveis de Saúde , Adulto , Fatores Etários , Idoso , Viés , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Caracteres Sexuais , Fatores SexuaisRESUMO
We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.
Assuntos
Biomarcadores/metabolismo , Colite Ulcerativa/genética , Doença de Crohn/genética , Proteínas da Matriz Extracelular/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Estudos de Coortes , Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Proteínas de Ligação ao GTP/genética , Antígenos HLA-A/genética , Proteínas de Homeodomínio/genética , Humanos , Subunidade p40 da Interleucina-12/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteína Adaptadora de Sinalização NOD2/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Interleucina/genética , Fatores de RiscoRESUMO
We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.