Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial.

We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18-1.37, P = 4 × 10-10, and HR per SD 1.35, 95% CI 1.16-1.58, P = 2 × 10-4, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 × 10-4). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years. When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci.

Morieri ML ，Gao H ，Pigeyre M ，Shah HS ，Sjaarda J ，Mendonca C ，Hastings T ，Buranasupkajorn P ，Motsinger-Reif AA ，Rotroff DM ，Sigal RJ ，Marcovina SM ，Kraft P ，Buse JB ，Wagner MJ ，Gerstein HC ，Mychaleckyj JC ，Parè G ，Doria A ... -  《-》

A genetic risk score of 45 coronary artery disease risk variants associates with increased risk of myocardial infarction in 6041 Danish individuals.

In Europeans, 45 genetic risk variants for coronary artery disease (CAD) have been identified in genome-wide association studies. We constructed a genetic risk score (GRS) of these variants to estimate the effect on incidence and clinical predictability of myocardial infarction (MI) and CAD. Genotype was available from 6041 Danes. An unweighted GRS was constructed by making a summated score of the 45 known genetic CAD risk variants. Registries provided information (mean follow-up = 11.6 years) on CAD (n = 374) and MI (n = 124) events. Cox proportional hazard estimates with age as time scale was adjusted for sex, BMI, type 2 diabetes mellitus and smoking status. Analyses were also stratified either by sex or median age (below or above 45 years of age). We estimated GRS contribution to MI prediction by assessing net reclassification index (NRI) and integrated discrimination improvement (IDI) added to the European SCORE for 10-year MI risk prediction. The GRS associated significantly with risk of incident MI (allele-dependent hazard ratio (95%CI): 1.06 (1.02-1.11), p = 0.01) but not with CAD (p = 0.39). Stratification revealed association of GRS with MI in men (1.06 (1.01-1.12), p = 0.02) and in individuals above the median of 45.11 years of age (1.06 (1.00-1.12), p = 0.03). There was no interaction between GRS and gender (p = 0.90) or age (p = 0.83). The GRS improved neither NRI nor IDI. The GRS of 45 GWAS identified risk variants increase the risk of MI in a Danish cohort. The GRS did not improve NRI or IDI beyond the performance of conventional European SCORE risk factors.

Krarup NT ，Borglykke A ，Allin KH ，Sandholt CH ，Justesen JM ，Andersson EA ，Grarup N ，Jørgensen T ，Pedersen O ，Hansen T ... -  《-》

Genetic predisposition to coronary artery disease is predictive of recurrent events: a Chinese prospective cohort study.

Evidence of the effects of genetic risk score (GRS) on secondary prevention is scarce and mixed. We investigated whether coronary artery disease (CAD) susceptible loci can be used to predict the risk of major adverse cardiovascular events (MACEs) in a cohort with acute coronary syndromes (ACSs). A total of 1667 patients hospitalized with ACS were enrolled and prospectively followed for a median of 2 years. We constructed a weighted GRS comprising 79 CAD risk variants and investigated the association between GRS and MACE using a multivariable cox proportional hazard regression model. The incremental value of adding GRS into the prediction model was assessed by integrated discrimination improvement (IDI) and decision curve analysis (DCA). In the age- and sex-adjusted model, each increase in standard deviation in the GRS was associated with a 33% increased risk of MACE (hazard ratio: 1.33; 95% confidence interval: 1.10-1.61; P = 0.003), with this association not attenuating after further adjustment for traditional cardiovascular risk factors. The addition of GRS to a prediction model of seven clinical risk factors and EPICOR prognostic model slightly improved risk stratification for MACE as calculated by IDI (+1.7%, P = 0.006; +0.3%, P = 0.024, respectively). DCA demonstrated positive net benefits by adding GRS to other models. GRS was associated with MACE after multivariable adjustment in a cohort comprising Chinese ACS patients. Future studies are needed to validate our results and further evaluate the predictive value of GRS in secondary prevention.

Jiang J ，Zheng Q ，Han Y ，Qiao S ，Chen J ，Yuan Z ，Yu B ，Ge L ，Jia J ，Gong Y ，Wang Z ，Chen D ，Zhang Y ，Huo Y ... -  《-》

Incremental value of a genetic risk score for the prediction of new vascular events in patients with clinically manifest vascular disease.

Several genetic markers are related to incidence of cardiovascular events. We evaluated whether a genetic risk score (GRS) based on 30 single-nucleotide-polymorphisms associated with coronary artery disease (CAD) can improve prediction of 10-year risk of new cardiovascular events in patients with clinical manifest vascular disease. In 5742 patients with symptomatic vascular disease enrolled in the SMART study, we developed Cox regression models based on the SMART Risk Score (SRS) and based on the SRS plus the GRS in all patients, in patients with a history of acute arterial thrombotic events and in patients with a history of more stable atherosclerosis and without CAD. The discriminatory ability was expressed by the c-statistic. Model calibration was evaluated by calibration plots. The incremental value of adding the GRS was assessed by net reclassification index (NRI) and decision curve analysis. During a median follow-up of 6.5 years (IQR4.0-9.5), the composite outcome of myocardial infarction, stroke, or vascular death occurred in 933 patients. Hazard ratios of GRS ranging from 0.86 to 1.35 were observed. The discriminatory capacity of the SRS for prediction of 10-year risk of cardiovascular events was fairly good (c-statistic 0.70, 95%CI 0.68-0.72), similar to the model based on the SRS plus the GRS. Calibration of the models based on SRS and SRS plus GRS was adequate. No increase in c-statistics, categorical NRIs and decision curves was observed when adding the GRS. The continuous NRI improved only in patients with stable atherosclerosis (0.14, 95%CI 0.03-0.25), increasing further excluding patients with a history of CAD (0.21, 95%CI 0.06-0.36). In patients with symptomatic vascular disease, a GRS did not improve risk prediction of 10-year risk of cardiovascular events beyond clinical characteristics. The GRS might improve risk prediction of first vascular events in the subgroup of patients with a history of stable atherosclerosis.

Weijmans M ，de Bakker PI ，van der Graaf Y ，Asselbergs FW ，Algra A ，Jan de Borst G ，Spiering W ，Visseren FL ，SMART Study Group ... -  《-》

Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk.

The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p < 5*10(-8)) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p < 0.05), more than expected by chance (p = 5.0*10(-5)). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973-1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p = 7.2*10(-10) vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting.

Jansen H ，Loley C ，Lieb W ，Pencina MJ ，Nelson CP ，Kathiresan S ，Peloso GM ，Voight BF ，Reilly MP ，Assimes TL ，Boerwinkle E ，Hengstenberg C ，Laaksonen R ，McPherson R ，Roberts R ，Thorsteinsdottir U ，Peters A ，Gieger C ，Rawal R ，Thompson JR ，König IR ，CARDIoGRAM consortium ，Vasan RS ，Erdmann J ，Samani NJ ，Schunkert H ... -  《-》