Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease.

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 ∼456,000 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.

Use of coronary computed tomography or polygenic risk scores to prompt action to reduce coronary artery disease risk: the CAPAR-CAD trial.

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.

Eicosanoid Inflammatory Mediators Are Robustly Associated With Blood Pressure in the General Population.

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 (P

Genome-Wide Association Studies and Risk Scores for Coronary Artery Disease: Sex Biases.

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.

Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease.

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.

A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.

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.