Utility Of Genetic Risk Score Research Articles

The relationship between familial-genetic risk and pharmacological treatment in a Swedish national sample of patients with major depression, bipolar disorder, and schizophrenia.

Using Swedish registers, we examine whether the prescription of and the response to antidepressants (AD), mood stabilizers (MS), and antipsychotics (AP) in the treatment of, respectively, major depression (MD), bipolar disorder (BD), and schizophrenia (SZ), are influenced by familial-genetic risk. We examined individuals born in Sweden 1960-1995 with a first diagnosis of MD (n = 257,177), BD (n = 23,032), and SZ (n = 4248) from 2006 to 2018. Drug classes and Defined Daily Dose (DDD) were obtained from the Pharmacy register using the Anatomical Therapeutic Chemical system. We utilized the Familial Genetic Risk Scores (FGRS) calculated from morbidity risks in first- through fifth degree relatives. Treatment with antidepressants (AD) in MD, mood-stabilizers (MS) in BD, and antipsychotics (AP) in SZ were associated with significantly higher disorder-specific familial-genetic risks. Using dosage trajectory analysis of AD, MS, and AP treatment for MD, BD, and SZ, respectively, familial-genetic risk was positively associated with higher and/or increasing drug dosages over time. For MD and BD, examining cases started on the most common pharmacologic treatment class (SSRIs for MD and "other anti-epileptics" for BD), familial-genetic risks were significantly lower in those who did not versus did later receive treatment from other AD and MS classes, respectively. Higher familial-genetic risk for BD predicted switching AD medication in cases of MD. Among pharmacologically treated cases of BD, familial-genetic risk was significantly higher for those treated with lithium. In a large population-based patient cohort, we found evidence of a wide-spread association between higher familial-genetic risk and i) increased likelihood of receiving pharmacologic treatment but 2) responding more poorly to it-as indicated by a switching of medications -- and/or requiring higher doses. Further investigations into the clinical utility of genetic risk scores in the clinical managements of MD, BD, and SZ are warranted.

Genetics of T2DM and Its Chronic Complications: Are We Any Closer to the Individual Prediction of Genetic Risk?

Type 2 diabetes mellitus (T2DM) is a complex disease that has risen in global prevalence over recent decades, resulting in concomitant and enormous socio-economic impacts. In addition to the well-documented risk factors of obesity, poor dietary habits and sedentary lifestyles, genetic background plays a key role in the aetiopathogenesis of diabetes and the development of associated micro- and macro-vascular complications. Recent advances in genomic research, notably next-generation sequencing and genome-wide association studies, have greatly improved the efficiency with which genetic backgrounds to complex diseases are analysed. To date, several hundred single-nucleotide polymorphisms have been associated with T2DM or its complications. Given the polygenic background to T2DM (and numerous other complex diseases), the degree of genetic predisposition can be treated as a “continuous trait” quantified by a genetic risk score. Focusing mainly on the Central European population, this review summarizes recent state-of-the-art methods that have enabled us to better determine the genetic architecture of T2DM and the utility of genetic risk scores in disease prediction.

Coexistence of inhibitory and activating killer-cell immunoglobulin-like receptors to the same cognate HLA-C2 and Bw4 ligands confer breast cancer risk

Human leukocyte antigen (HLA) class I-specific killer-cell immunoglobulin-like receptors (KIR) regulate natural killer (NK) cell function in eliminating malignancy. Breast cancer (BC) patients exhibit reduced NK-cytotoxicity in peripheral blood. To test the hypothesis that certain KIR-HLA combinations impairing NK-cytotoxicity predispose to BC risk, we analyzed KIR and HLA polymorphisms in 162 women with BC and 278 controls. KIR-Bx genotypes increased significantly in BC than controls (83.3% vs. 71.9%, OR 1.95), and the increase was more pronounced in advanced-cancer (OR 5.3). No difference was observed with inhibitory KIR (iKIR) and HLA-ligand combinations. The activating KIR (aKIR) and HLA-ligand combinations, 2DS1 + C2 (OR 2.98) and 3DS1 + Bw4 (OR 2.6), were significantly increased in advanced-BC. All patients with advanced-cancer carrying 2DS1 + C2 or 3DS1 + Bw4 also have their iKIR counterparts 2DL1 and 3DL1, respectively. Contrarily, the 2DL1 + C2 and 3DL1 + Bw4 pairs without their aKIR counterparts are significantly higher in controls. These data suggest that NK cells expressing iKIR to the cognate HLA-ligands in the absence of putative aKIR counterpart are instrumental in antitumor response. These data provide a new framework for improving the utility of genetic risk scores for individualized surveillance.

The Utility of Genetic Risk Score to Improve Performance of FRAX for Fracture Prediction in US Postmenopausal Women.

The ability of the fracture risk assessment tool (FRAX) in discriminating fracture and non-fracture in postmenopausal women remains suboptimal. Adding a genetic profile may improve the performance of FRAX. Three genetic risk scores (GRSs) (GRS_fracture, GRS_BMD, GRS_eBMD) were calculated for each participant in the Women's Health Initiative Study (n = 23,981), based on the summary statistics of three comprehensive osteoporosis-related genome-wide association studies (GWAS). The primary outcomes were incident major osteoporotic fracture (MOF) and hip fracture (HF). The association between each GRS and fracture risk were evaluated in separate Cox Proportional Hazard models, with FRAX clinical risk factors adjusted for. The discrimination ability of each model was assessed using Area Under the Curve (AUC). The predictive improvement attributable to each GRSs was assessed using the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI). GRS_BMD and GRS_eBMD were significantly associated with MOF and HF risk, independent of the base FRAX risk factors. Compare to the base FRAX model, the models with GRS_fracture, GRS_BMD, and GRS_eBMD improved the reclassification of MOF by 0.5% (95% CI, 0.2% to 0.9%, p = p < .01), 0.3% (95% CI, 0.1% to 0.6%, p = 0.01), and 2.1% (95% CI, 0.3% to 2.8%, p < .01), respectively. Similar results were also observed when using HF as an outcome. Our study suggested that the addition of genetic profiles provide limited improvements in the reclassification of FRAX for MOF and HF.

Assessing the clinical utility of genetic risk scores for targeted cancer screening

BackgroundGenome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention.MethodsThis clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40–70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups.ResultsThe median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants’ reported optimism about their future health neither before nor after receiving GRS results.ConclusionsGenetic risk scores that quantify an individual’s risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.

Additional value of a combined genetic risk score to standard cardiovascular stratification.

The utility of genetic risk scores (GRS) as independent risk predictors remains inconclusive. Here, we evaluate the additive value of a multi-locus GRS to the Framingham risk score (FRS) in coronary artery disease (CAD) risk prediction. A total of 2888 individuals (1566 coronary patients and 1322 controls) were divided into three subgroups according to FRS. Multiplicative GRS was determined for 32 genetic variants associated to CAD. Logistic Regression and Area Under the Curve (AUC) were determined first, using the TRF for each FRS subgroup, and secondly, adding GRS. Different models (TRF, TRF+GRS) were used to classify the subjects into risk categories for the FRS 10-year predicted risk. The improvement offered by GRS was expressed as Net Reclassification Index and Integrated Discrimination Improvement. Multivariate analysis showed that GRS was an independent predictor for CAD (OR = 1.87; p<0.0001). Diabetes, arterial hypertension, dyslipidemia and smoking status were also independent CAD predictors (p<0.05). GRS added predictive value to TRF across all risk subgroups. NRI showed a significant improvement in all categories. In conclusion, GRS provided a better incremental value in intermediate subgroup. In this subgroup, inclusion of genotyping may be considered to better stratify cardiovascular risk.

Genetic risk scores and family history as predictors of schizophrenia in Nordic registers.

Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other. We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes. Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility. Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.

The influence of genetic susceptibility and calcium plus vitamin D supplementation on fracture risk1–3

Background: Fracture is a complex trait, affected by both genetic and environmental factors. A meta-analysis of genome-wide association studies (GWASs) identified multiple bone mineral density (BMD) and fracture-associated loci.Objective: We conducted a study to evaluate whether fracture genetic risk score (Fx-GRS) and bone mineral density genetic risk score (BMD-GRS) modify the association between the intake of calcium with vitamin D (CaD) and fracture risk.Design: Data from 5823 white postmenopausal women from the Women’s Health Initiative CaD randomized trial were included. Participants received 1000 mg elemental Ca with 400 IU vitamin D3/d or placebo (median follow-up: 6.5 y). Total fracture was defined as first fracture of any type. We computed the Fx-GRS with 16 fracture- and BMD-associated variants, and the BMD-GRS with 50 BMD-associated variants. We used Cox regression and a case-only approach to test for multiplicative interaction. Additive interaction was assessed with the relative excess risk due to interaction (RERI). We analyzed genetic risk score as a continuous variable and a categorical variable based on quartile (quartile 1, quartiles 2–3, and quartile 4).Results: We observed no interaction between the Fx-GRS and CaD on fracture risk; however, we observed a significant multiplicative interaction between the BMD-GRS and CaD assignment (P-interaction = 0.01). In addition, there was a significant negative additive interaction between placebo assignment and higher BMD-GRS: quartiles 2–3, PRERI = 0.03; quartile 4, PRERI = 0.03. In a stratified analysis, the protective effect of CaD on fracture risk was observed in women in the lowest BMD-GRS quartile (HR: 0.60, 95% CI: 0.44, 0.81) but not in women with a higher BMD-GRS.Conclusions: We observed significant effects of CaD intake on fracture risk only in women with the lowest genetic predisposition to low BMD. Future large-scale studies with functional characterization of GWAS findings are warranted to assess the utility of genetic risk score in analysis of risks and benefits of CaD for bone.

Prostate cancer meta-analysis from more than 145,000 men to identify 65 novel prostate cancer susceptibility loci.

1 Background: Currently genome-wide association studies (GWAS) have identified over 100 prostate cancer (PrCa) susceptibility loci, capturing 33% of the PrCa familial relative risk (FRR) in Europeans. To identify further susceptibility variants, we conducted a PrCa GWAS, larger than previous studies, comprising ~49,000 cases and ~29,000 controls among individuals of European and Asian descent using the OncoArray, a platform consisting of a 260K GWAS backbone and 310K custom content selected from previous GWAS and fine-mapping studies of multiple cancers ( http://epi.grants.cancer.gov/oncoarray/ ). Methods: Genotypes from the OncoArray were used to impute genotypes from ~70M variants using the October 2014 release of the 1000 genomes project as a reference, and then combined with several previous PrCa GWAS of European ancestry: UK stage 1 (1,906 cases/1,934 controls) and stage 2 (3,888 cases/3,956 controls); CaPS 1 (498 cases/502 controls) and CaPS 2 (1,483 cases/519 controls); BPC3 (2,137 cases/3,101 controls); NCI PEGASUS (4,622 cases/2,954 controls); and iCOGS (21,209 cases/ 20,440 controls). Risk analyses for overall PrCa risk, aggressive PrCa (several definitions defined by PrCa clinical characteristics), and Gleason score were performed. Logistic and linear regression summary statistics were meta-analysed using an inverse variance fixed effect approach. Results: We identified novel loci significantly associated ( P &lt; 5.0x10-8) with overall PrCa (N = 65). Our novel findings are comprised of several missense variants, including a SNP in the ATM gene - a key member of the DNA repair pathway. When combined multiplicatively, the 65 novel PrCa loci identified here increases the captured heritability of PrCa, explaining 38.5% of the FRR when combining novel and previously identified PrCa loci. Conclusions: In risk stratification, men in the top 1% of the genetic risk score group have a relative risk of 5.6 fold for developing PrCa compared with the median risk group. These results will improve the utility of genetic risk scores for targeted screening and prevention for prostate cancer.

Abstract 2565: Prostate cancer GWAS from more than 89,000 men identifies more than 30 novel prostate cancer susceptibility loci

Abstract Genome-wide association studies (GWAS) and fine-mapping efforts have identified over 100 loci associated with prostate cancer susceptibility. Combined multiplicatively, these loci capture 33% of the familial risk for prostate cancer among European-ancestral populations. In order to identify novel prostate cancer susceptibility loci we conducted a GWAS involving over 53,000 prostate cancer cases and 36,000 controls using the OncoArray that includes a 260K GWAS backbone and a custom portion of 310K SNPs developed from previous GWAS and fine-mapping studies of multiple cancer types (http://epi.grants.cancer.gov/oncoarray/). Following standard quality control procedures, the prostate cancer OncoArray genotyped data were imputed using the October 2014 release of the 1000 genomes project data as a reference and analyzed by participating study for overall and advanced prostate cancer using logistic regression. The study-specific results were combined using inverse variance fixed effect meta-analysis. Regions surrounding previously associated variants (+/- 500kb of the reported index variant) were excluded to identify novel associations. In the OncoArray meta-analysis, we identified more than 30 novel loci significantly associated (P&amp;lt;5.0×10-8) with overall, advanced (Gleason ≥8, death from PrCa, PSA&amp;gt;100, or disease stage “Distant”), or early-onset (≤55 years of age) prostate cancer. Previous GWAS of prostate cancer are being imputed to the latest release of the 1000 genomes project to enhance our statistical power for novel discovery. In total our overall meta-analysis will incorporate over 176,000 individuals of European ancestry - more than 95,000 prostate cancer cases and 79,000 controls. The current results, as well as the larger ongoing meta-analysis, provide further insight into the underlying mechanisms of prostate cancer carcinogenesis and will improve the utility of genetic risk scores for targeted screening and prostate cancer prevention. Citation Format: Fredrick R. Schumacher, Ali A. Al Olama, Sonja I. Berndt, Fredrik Wiklund, David V. Conti, Mahbubl Ahmed, Sarah Benlloch, Douglas F. Easton, Peter Kraft, Stephen J. Chanock, Brian E. Henderson, Zsofia Kote-Jarai, Christopher A. Haiman, Rosalind A. Eeles. Prostate cancer GWAS from more than 89,000 men identifies more than 30 novel prostate cancer susceptibility loci. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2565.

Utility of blood pressure genetic risk score in admixed Hispanic samples.

Hypertension is strongly influenced by genetic factors. Although hypertension prevalence in some Hispanic sub-populations is greater than in non-Hispanic whites, genetic studies on hypertension have focused primarily on samples of European descent. A recent meta-analysis of 200,000 individuals of European descent identified 29 common genetic variants that influence blood pressure, and a genetic risk score derived from the 29 variants has been proposed. We sought to evaluate the utility of this genetic risk score in Hispanics. The sample set consists of 1994 Hispanics from two cohorts: the Northern Manhattan Study (primarily Dominican/Puerto Rican) and the Miami Cardiovascular Registry (primarily Cuban/South American). Risk scores for systolic and diastolic blood pressure were computed as a weighted sum of the risk alleles, with the regression coefficients reported in the European meta-analysis used as weights. Association of risk score with blood pressure was tested within each cohort, adjusting for age, age squared, sex, and BMI. Results were combined using an inverse-variance meta-analysis. The risk score was significantly associated with blood pressure in our combined sample (p = 5.65 × 10−4 for systolic and p = 1.65 × 10−3 for diastolic) but the magnitude of the regression coefficients varied by degree of European, African, and Native American admixture. Further studies among other Hispanic sub-populations are needed to elucidate the role of these 29 variants and identify additional genetic and environmental factors contributing to blood pressure variability in Hispanics.

Clinical validity and utility of genetic risk scores in prostate cancer.

Current issues related to prostate cancer (PCa) clinical care (e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa) call for risk assessment tools that can be combined with family history (FH) to stratify disease risk among men in the general population. Since 2007, genome-wide association studies (GWASs) have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss (1) the validity of these PCa risk-associated SNPs, individually and collectively; (2) the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score (GRS); (3) the adequate number of SNPs needed for risk assessment; (4) reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, (5) risk assessment for men from various racial groups, and (6) the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs and GRS in risk assessment among men with or without FH. PCa risk-associated SNPs are not intended for diagnostic use; rather, they should be used the same way as FH. Combining GRS and FH can significantly improve the performance of risk assessment. Improved risk assessment may have important clinical utility in targeted PCa testing. However, clinical trials are urgently needed to evaluate this clinical utility as well as the acceptance of GRS by patients and physicians.

Replication of a genetic risk score for venous thromboembolism in whites but not in African Americans

ESSENTIALS: There is little prospective information on genetic risk scores to predict venous thromboembolism (VT). Community based cohort followed a median of 22.6 years for VT occurrence. A 5-SNP risk score identified whites at risk of VT, but not African Americans. The utility of genetic risk scores for VT is yet to be established. Case-control studies have created genetic risk scores of single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) and documented their ability to predict VTE, but prospective data are lacking. To test the ability of a genetic risk score to predict VTE incidence in a prospective study, particularly in African Americans. We computed a previously proposed genetic risk score, based on five established VTE SNPs in the F5, F2, ABO, FGG, and F11 genes, in 9520 whites and 3049 African Americans initially free of VTE. We followed them a median of 22.6 years for VTE occurrence (n = 380 events in whites and n = 187 in African Americans). In whites, the five-SNP weighted genetic risk score ranged from 0 to 5.8, and VTE risk increased 1.41-fold (95% confidence interval [CI] 1.27-fold to 1.56-fold) per allele increment. In African Americans, the weighted genetic risk score ranged from 0 to 4.6 and the hazard ratio per risk allele was 1.14 (95% CI 0.94-1.38), with adjustment for 10 principal components of ancestry. The area under the receiver operating characteristic curve for 20-year prediction of VTE from the weighted genetic risk score was 0.59 (95% CI 0.56-0.63) in whites and 0.56 (95% CI 0.51-0.61) in African Americans. Adding non-genetic factors increased the area under the curve to 0.67 in whites and to 0.66 in African Americans. Higher values for a five-SNP genetic risk score helped identify white adults at risk of VTE. The genetic risk score did not identify future VTE occurrence in African Americans.

Abstract 10264: Additional Value of a Combined Genetic Score to Framingham Risk Score

Introduction: Previous studies consistently reported statistically significant relative risk for coronary artery disease (CAD) with multiple genes. The utility of genetic risk scores (GRS) as additive risk predictors to standard stratification like Framingham risk score (FS) remains inconclusive. Objectives: To evaluate the ability of a multiloci GRS to provide additive value to 10 year risk FS subgroups (low risk &lt;5%, intermediate risk 5-20%, high risk &gt;20%) in a south European sample. Methods: Case-control study of 2555 individuals, 1321 (51.7%) coronary patients and 1234 (48.3%) of controls without coronary disease with a mean age of 52±8.3 years divided in three groups according to FS (FS&lt;5, n=403, 53.3% male, FS 5-20, n=1657, 78% male and FS&gt;20, n= 495, 89.7% male). The multiloci GRS was determined with specific primers of 29 different genetic variants associated to atherosclerotic/CAD disease. A multiplicative model was used based on risk multiplication (odds ratio - OR) of each genotype. Multivariate analysis and respective ROC curves and area under curve (AUC) were performed for each Framingham risk subgroup. The analysis was repeated adding GRS and pairwise comparison of the two ROC Curve was done by the DeLong test. Results: By multivariate analysis GRS was an independent predictor for CAD (OR=2.05; 1.66-2.54, p&lt;0.0001). Diabetes, arterial hypertension, dyslipidemia and smoking (OR= 3.07 (2.47-3.80); OR=2.07 (1.73-2.49); OR=3.1 (2.37-4.07); OR=3.11 (2.58-3.74); all p&lt;0.0001) were also independent CAD predictors. GRS added significant predictive value to Framingham score across the intermediate (0.70 to 0.73 (p&lt;0.0001) and high risk group from 0.68 to 0.72 (p=0.005). Conclusion: GRS proved to add significant incremental value only in intermediate and high risk subgroups. In these subgroups, the inclusion of genotyping may be considered to better clarify cardiovascular risk.

Utility of a genetic risk score to predict recurrent cardiovascular events 1 year after an acute coronary syndrome: A pooled analysis of the RISCA, PRAXY, and TRIUMPH cohorts.

Limited evidence exists regarding the utility of genetic risk scores (GRS) in predicting recurrent cardiovascular events after acute coronary syndrome (ACS). We sought to determine whether a GRS would predict early recurrent cardiovascular events within 1 year of ACS. Participants admitted with acute coronary syndromes from the RISCA, PRAXY, and TRIUMPH cohorts, were genotyped for 30 single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) or myocardial infarction (MI) in prior genome wide association studies. A 30 SNP CAD/MI GRS was constructed. The primary endpoint was defined as all-cause mortality, recurrent ACS or cardiac re-hospitalization within 1 year of ACS admission. Results across all cohorts for the 30 SNP CAD/MI GRS were pooled using a random-effects model. There were 1040 patients from the RISCA cohort, 691 patients from the PRAXY cohort, and 1772 patients from the TRIUMPH cohort included in the analysis and 389 occurrences of the primary endpoint of recurrent events at 1-year post-ACS. In unadjusted and fully adjusted analyses, a 30 SNP GRS was not significantly associated with recurrent events (HR per allele 0.97 (95%CI 0.91-1.03) for RISCA, HR 0.99 (95%CI 0.93-1.05) for PRAXY, 0.98 (95%CI 0.94-1.02) for TRIUMPH, and 0.98 (95%CI 0.95-1.01) for the pooled analysis). Addition of this GRS to the GRACE risk model did not significantly improve risk prediction. The 30 MI SNP GRS was not associated with recurrent events 1-year post ACS in pooled analyses across cohorts and did not improve risk discrimination or reclassification indices. Our results suggest that the genetic etiology of early events post-ACS may differ from later events.

UTILITY OF A LDL CHOLESTEROL GENETIC RISK SCORE TO PREDICT RECURRENT CARDIOVASCULAR EVENTS AFTER ACUTE CORONARY SYNDROME

controls (c (1) 1⁄4 7.24, p 2-fold more patients achieving recommended target LDL-c levels. This could have major implications for prevention of cardiovascular disease in Canada. AstraZeneca