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 ... -  《-》

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 ... -  《-》

Incremental predictive value of 152 single nucleotide polymorphisms in the 10-year risk prediction of incident coronary heart disease: the Rotterdam Study.

To examine the incremental predictive value of genetic risk scores of coronary heart disease (CHD) in the 10-year risk prediction of incident CHD. In 5899 subjects, we used 152 single nucleotide polymorphisms (SNPs) associated with coronary artery disease by the CARDIoGRAMplusC4D consortium to construct three weighted genetic risk scores: (i) GRS(gws) based on 49 genome-wide significant SNPs; (ii) GRS(fdr) based on 103 suggestively associated SNPs; and (iii) GRS(all) based on all 152 SNPs. We examined the changes in discrimination and reclassification of incident CHD when adding the genetic risk scores to models including traditional risk factors. We repeated the analysis for prevalent CHD. The genetic risk scores were associated with incident CHD despite adjustment for traditional risk factors and family history: participants had a 13% higher rate of CHD per standard deviation increase in GRS(all). GRS(all )improved the C-statistic by 0.006 [95% confidence interval (CI): 0.000, 0.013] beyond age and sex, 0.003 (95% CI: -0.001, 0.008) beyond traditional risk factors and 0.003 (95% CI: -0.001, 0.007) beyond traditional risk factors and family history. The genetic risk scores did not improve reclassification. GRS(all) strongly improved both discrimination and reclassification of prevalent CHD, even beyond traditional risk factors and family history, with a C-statistic improvement of 0.009 (0.003, 0.015). Although the genetic risk scores based on 152 SNPs were associated with incident CHD, they did not improve risk prediction. This discrepancy may be the result of SNP discovery for prevalent rather than incident CHD, since the SNPs do improve prediction for prevalent disease.

de Vries PS ，Kavousi M ，Ligthart S ，Uitterlinden AG ，Hofman A ，Franco OH ，Dehghan A ... -  《-》

The impact of susceptibility loci for coronary artery disease on other vascular domains and recurrence risk.

Tragante V ，Doevendans PA ，Nathoe HM ，van der Graaf Y ，Spiering W ，Algra A ，de Borst GJ ，de Bakker PI ，Asselbergs FW ，SMART study group ... -  《-》

Impact of carotid atherosclerosis loci on cardiovascular events.

Genome-wide association studies (GWAS) have identified six single-nucleotide polymorphisms (SNPs) related to carotid intima media thickness (cIMT) or plaque. However, whether these loci relate to other vascular diseases and subsequent vascular events is unclear. We tested six SNPs (rs4888378, rs11781551, rs445925, rs6601530, rs17398575 and rs1878406) for association with subclinical atherosclerotic measures (cIMT, plaque presence and ankle-brachial index), as well as ischemic stroke, abdominal aortic aneurysm, peripheral or coronary artery disease (CAD) in the Second Manifestations of ARTerial disease (SMART) cohort. Four SNPs were associated with cIMT and two with plaque (p < 0.05). One SNP was also significantly associated to CAD (rs1878406, OR = 1.24, 95% CI = 1.08-1.42, p = 2 × 10(-3)). A genetic risk score (GRS) based on the cIMT-related SNPs was associated to increased risk of cIMT itself (p = 1 × 10(-3)), but not to other secondary outcomes or vascular events during follow-up (p = 0.86). In addition to replicating previously published associations for cIMT, we confirmed a nominally significant effect between the GRS and cIMT.

Hemerich D ，van der Laan SW ，Tragante V ，den Ruijter HM ，de Borst GJ ，Pasterkamp G ，de Bakker PI ，Asselbergs FW ... -  《-》