Welcome to the EAS 2021 Interactive Program
The congress will officially run on EEST time zone (Eastern European Summer Time, Helsinki, CET+1)
Introduction (ID 1580)
Novel insight into the genetics of hypetriglyceridemia (ID 1289)
Polygenic and clinical risk scores and their impact on age of onset and prediction of cardiovascular diseases (ID 1290)
O012 - Evaluation of new Polygenic Risk Scores in the diagnosis of Familial Hypercholesterolemia (ID 830)
Abstract
Background and Aims
Whereas the identification of causal mutations leads to a molecular diagnosis of familial hypercholesterolemia (FH), it is now established that the cumulative effects of common SNPs on LDL-cholesterol (LDL-c) can phenocopy the FH conditions. Polygenic Risk Scores (PRSs) have been developed using few to millions of SNPs to identify patients with polygenic-FH. We here set up and compared the performance of several PRSs for the diagnosis of polygenic-FH.
Methods
Four PRSs for LDL-c were set up using PLINK, PRSice2, Lassossum and LDpred2 softwares, including 165 to 1633 SNPs sequenced using the Dysliseq panel. These PRSs were tested in 758 hypercholesterolemic patients, and 1082 French healthy controls and then compared with previously described PRSs. The fraction of LDL-c variance explained by PRSs was defined in controls and the ability of PRS to discriminate mutation negative patients (FH/M-) vs. healthy individuals was determined using ROC curves. Patients with PRSs > 95th percentile of controls were considered as polygenic-FH.
Results
The 165-SNP PRS developed with PLINK explains the highest part of LCL-c variance (adjusted R²: 0.187) and shows the best diagnosis ability (AUC: 0.759, significantly over performing previously-published PRSs: p-value < 1x10-5). Within FH/M- patients, 22% of polygenic forms were detected using this 165-SNP PRS versus 14% with the previously-published 12-SNP PRS (p-value: 5.41x10-5).
Conclusions
Notably, this new PRS improves the diagnosis ability and is compatible with routine genetic diagnosis. Indeed, the identification of polygenic-FH allows the etiologic diagnosis in FH/M- and the identification of an additional cause of hypercholesterolemia in FH/M+.
O013 - A multivariate analysis identifies genetic loci associated with atherosclerotic plaque composition and cardiovascular disease trajectory (ID 728)
Abstract
Background and Aims
From cross-sectional studies, we have learned that the composition of atherosclerotic plaques differs between individuals, and this contributes to the inter-individual differences in susceptibility to incident coronary and cerebral events. In pathological studies, the extent and type of atherosclerosis are commonly assessed based on histological plaque characteristics that are linked to plaque rupture and erosion. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases. We investigated the genetics of the plaque through multivariate and integrative genome-wide analyses (GWAS) of individual plaque characteristics.
Methods
We included carotid endarterectomy patients from the Athero-Express Biobank Study (n = 2,124) with high-density imputed data and extensive histochemical plaque phenotyping available. We used slideToolKit to quantify the number of endothelial cells, macrophages and smooth muscle cells (SMCs), and manually assessed the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. We ran GWAS on all traits correcting for age, sex, array used, and genetic ancestry.
Results
We identified 3 loci that significantly associate with CD68+ macrophages and ACTA2+ SMCs, p < 5x10-8. Statistical fine-mapping revealed 9 variants in the 95% credible set and functional annotation linked these to genes associated with malignant neoplasms, circulating cholesterol, and transmembrane proteins, suggesting an effect on cellular proliferation and cholesterol metabolism.
Conclusions
We provide evidence for 3 loci that modulate plaque composition through macrophages and smooth muscle cell plaque proliferation and cell-cell interactions.
O014 - Highly frequent variants hidden in the KIV-2 region of LPA regulate lipoprotein(a) concentrations and lower coronary artery disease risk (ID 196)
Abstract
Background and Aims
The lipoprotein(a) [Lp(a)] plasma concentration is largely determined by variation in the LPA gene. However, the repetitive KIV-2 domain is difficult to analyze by conventional PCR-based technologies. The KIV-2 variant 4733G>A is a novel and frequent putative splicing modifier but its function, impact on Lp(a) and coronary artery disease (CAD) risk and, importantly, its combined effect with the 4925G>A, another frequent functional KIV-2 variant, have not been characterized.
Methods
We typed the 4733G>A variant in the German Chronic Kidney Disease (GCKD) study (n=4,673) using a novel allele-specific assay. Its function was analyzed by minigene assays. Ethnic frequencies were assessed in 1000Genomes. Proxy SNPs were identified in GCKD and used to analyze the effect of 4733G>A and the combined effect with 4925G>A on CAD in UK Biobank (n=440,234).
Results
The 4733G>A variant has a carrier frequency of 38%, lowers Lp(a) by 14.0 mg/dL ([15.3-12.6], p=4.82e-184) and was the second strongest genetic factor after the apolipoprotein(a) isoforms. It is found in all isoforms and reduces the expression of the mutated allele. Frequencies differ strongly between ethnicities. Compound heterozygous carriers of 4733G>A and 4925G>A have low Lp(a) concentrations (median=7.2 mg/dL) with little variance left (IQR=4.6 mg/dL), independently from the isoform present. 4733G>A alone and compound heterozygosity with 4925G>A are associated with a significantly lower hazard ratio for CAD (0.91 [0.89-0.93], p<0.001 and 0.88 [0.84-0.93], p<0.001).
Conclusions
Hidden functional LPA variants profoundly modulate Lp(a) concentrations and CAD risk. Furthermore, the 4733G>A variant is a novel instrument to dissect the effect of Lp(a) concentrations and apolipoprotein(a) isoforms.
O015 - Plasma TSH Concentration and Risk of Cardiovascular Disease: A Mendelian Randomization Study of 105,224 Individuals from The General Population. (ID 210)
Abstract
Background and Aims
In observational studies, the association between plasma concentration of thyroid stimulating hormone (TSH) and cardiovascular disease outcomes is conflicting. Using Mendelian randomization, we tested the hypothesis that plasma TSH concentration is associated with risk of ischemic heart disease (IHD), myocardial infarction (MI), and atrial fibrillation (AF).
Methods
In a prospective cohort study of the general population, The Copenhagen General Population Study, including 105,224 individuals, we first tested whether plasma TSH concentration was associated observationally with risk of incident IHD, MI, and AF (=positive control). Subsequently, we tested the genetic association between an allele score weighted on plasma TSH concentrations and risk of the same endpoints.
Results
During a median follow-up of 7 years (0-13 years), 5,425 developed IHD, 2,148 had an incident MI, and 5,105 developed AF. Observationally, using multifactorially adjusted restricted cubic splines, low plasma TSH concentrations (<1.53mIU/L=median) were associated with an increased risk of IHD, MI, and AF. Hazard ratios (HR) increased gradually with lower TSH concentrations up to 1.11(0.99-1.23) for IHD, 1.22(1.03-1.43) for MI, and 1.22(1.10-1.35) for AF, comparing individuals with TSH concentrations in the lowest 5th (≤0.54mIU/L) versus >25th (>1.04mIU/L) percentile (=reference). In genetic analyses, comparing individuals with a gene score ≤5th percentile (who had 16% lower TSH concentrations), versus individuals with a gene score >50th percentile (=reference), HRs were 1.13(1.00-1.28) for IHD, 1.29(1.07-1.55) for MI, and 1.15(1.02-1.31) for AF.
Conclusions
Low plasma TSH concentrations are associated observationally and genetically with an increased risk of IHD, MI, and AF in the general population.
O016 - Mendelian randomization mediation analysis of the direct and indirect effects of adiposity on coronary artery disease (ID 1136)
Abstract
Background and Aims
Increased adiposity is associated with an increased risk of coronary artery disease (CAD). Whether adiposity has a direct causal effect on the risk of CAD, or whether the effect of adiposity on CAD is mediated indirectly through the effect of adiposity on other risk factors is unknown.
Methods
We constructed a body mass index (BMI) instrumental variable genetic score composed of 96 variants associated with BMI. We used this instrument to conduct a multivariable Mendelian randomization (MR) mediation analysis to estimate the direct and indirect effects of BMI on CAD. The study included individual level data on 445,774 participants including 23,032 cases of CAD and 28,563 cases of type II diabetes (T2D); and summary data on up to 877,643 participants including 63,746 cases of CAD and 26,676 cases of T2D.
Results
A one unit increase in BMI was associated with a 7% increased odds of CAD (OR:1.07; 95%CI:1.05-1.09, p=1.6E-10), a 25% increased odds of T2D (OR:1.25, 95%CI:1.23-1.28, p=2.2E-131); and 0.34 mmHg increase in systolic blood pressure (SBP) (95%CI:0.25-0.42, p=8.5E-15). A one unit increase in BMI was also associated with a 0.02 mmol/L increase in triglycerides (95%CI:0.02-0.03, p=4.9E-21), but not with increased apolipoprotein B levels. In MR mediation analyses, 80.0% of the effect of BMI on the risk of CAD was mediated through BMI induced increases in SBP (29.6%) and T2D risk (50.4%).
Conclusions
The vast majority of the effect of increased BMI on the risk of CAD appears to be mediated indirectly through the effect of BMI on SBP and T2D.