Abstract 13702: A Novel Genetic Risk Score Predicts Ischemic Stroke in Patients With Cardiometabolic Disease

Introduction: Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for first ischemic stroke after accounting for traditional risk factors in four clinical trials across the spectrum of cardiometabolic disease. Methods: Subjects who had consented for genetic testing, were of European ancestry, and had no prior history of stroke from the SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. A recently validated GRS composed of 36 SNPs associated with ischemic stroke was calculated in each patient. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for age, sex, ancestry, hypertension, hyperlipidemia, smoking, diabetes mellitus, atrial fibrillation, coronary artery disease, and congestive heart failure. Results: In 23,089 subjects across the four trials, a total of 313 ischemic strokes occurred over a median follow-up of 3 years. Those with higher genetic risk were at significantly increased risk for ischemic stroke with an adjusted HR per 1-SD GRS of 1.12 (1.004-1.25; p=0.043). Individuals in the top 10% of genetic risk had a 42% greater hazard for ischemic stroke than those in the lower 90% of genetic risk (adjusted HR 1.42 [1.03-1.97]; p=0.034). The magnitude of risk conferred by high genetic risk was similar or greater than the risk provided by well-established clinical risk factors (Figure). Conclusions: Across four large clinical trials of subjects with cardiometabolic disease, a 36-SNP GRS was a strong, independent predictor of first ischemic stroke. The risk of stroke was particularly high in patients in the top 10% of genetic risk.

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Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients with Cardiometabolic Disease

Circulation ◽

10.1161/circulationaha.120.051927 ◽

2020 ◽

Author(s):

Nicholas A. Marston ◽

Parth N. Patel ◽

Frederick K. Kamanu ◽

Francesco Nordio ◽

Giorgio M. Melloni ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Genetic Risk ◽

Genetic Risk Score ◽

Clinical Risk Factors ◽

Cardiometabolic Disease ◽

Clinical Risk ◽

Hazard Ratios ◽

Increased Risk

Background: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in five trials across the spectrum of cardiometabolic disease. Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48, SOLID-TIMI 52, SAVOR-TIMI 53, PEGASUS-TIMI 54, and FOURIER trials were included in this analysis. A set of 32 SNPs associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. Results: In 51,288 subjects across the five trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, increasing genetic risk was strongly and independently associated with increased risk for ischemic stroke (p-trend=0.009). When compared to individuals in the lowest third of genetic risk, individuals in the middle and top tertiles of genetic risk had adjusted hazard ratios of 1.15 (95% CI 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted HR for the top versus lowest tertile of 1.27 (95% CI 1.04-1.53), compared with an adjusted HR of 1.06 (95% CI 0.81-1.41) in subjects with prior stroke. In an exploratory analysis of patients with atrial fibrillation and CHA 2 DS 2 -VASc of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA 2 DS 2 -VASc of 3. Conclusions: Across a broad spectrum of subjects with cardiometabolic disease, a 32-SNP GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA 2 DS 2 -VASc scores, the GRS identified patients with risk comparable to those with higher CHA 2 DS 2 -VASc scores.

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Combined Effects of MMP-7, MMP-8 and MMP-26 on the Risk of Ischemic Stroke

Journal of Clinical Medicine ◽

10.3390/jcm8112011 ◽

2019 ◽

Vol 8 (11) ◽

pp. 2011

Author(s):

Fang-I Hsieh ◽

Hung-Yi Chiou ◽

Chaur-Jong Hu ◽

Jiann-Shing Jeng ◽

Huey-Juan Lin ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Genetic Risk ◽

Genetic Risk Score ◽

Weighted Average ◽

Combined Effects ◽

Cvd Risk Factors ◽

Cvd Risk ◽

Increased Risk ◽

Weighted Genetic Risk Score

Ischemic stroke (IS) is multifactorial causation combining with traditional cardiovascular disease (CVD) and genetic risk factors. Combined effects of MMP-7, MMP-8 and MMP-26 on the risk of IS remain incompletely understood. We aimed to assess individual and joint effects for IS risk by weighted genetic risk score (wGRS) from these three genes and traditional CVD risk factors. A case-control study including 500 cases with IS and 500 stroke-free healthy controls frequency-matched with cases by age and sex was conducted. The wGRS was a weighted average of the number of risk genotype across selected SNPs from MMP-7, MMP-8 and MMP-26. Multivariate logistic regression models were used to analyze the relationship between wGRS and risk of IS. A wGRS in the second tertile was associated with a 1.5-fold increased risk of IS compared with the lowest tertile after adjusting for traditional CVD risk factors. Compared to subjects with low genetic and low modifiable CVD risk, those with high genetic and high modifiable CVD risk had the highest risk of IS (adjusted-OR = 5.75). In conclusion, higher wGRS was significantly associated with an increased risk for IS. A significant interaction between genetic and traditional CVD risk factors was also found on the risk of IS.

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Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003006 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Nicholas A. Marston ◽

Giorgio E.M. Melloni ◽

Yared Gurmu ◽

Marc P. Bonaca ◽

Frederick K. Kamanu ◽

...

Keyword(s):

Risk Factors ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Risk Groups ◽

Clinical Risk Factors ◽

Cardiometabolic Disease ◽

Polygenic Risk Score ◽

Clinical Risk ◽

History Of

Background: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality and has a known genetic contribution. We tested the performance of a genetic risk score for its ability to predict VTE in 3 cohorts of patients with cardiometabolic disease. Methods: We included patients from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trials (history of a major atherosclerotic cardiovascular event, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE genetic risk score based on 297 single nucleotide polymorphisms with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared with available clinical risk factors (age, obesity, smoking, history of heart failure, and diabetes) and common monogenic mutations. Results: A total of 29 663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles ( P -trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI, 1.23–2.89; P =0.004) and 2.70-fold (95% CI, 1.81–4.06; P <0.0001) higher risk of VTE compared with patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the genetic risk score was associated with a 47% (95% CI, 29–68) increased risk of VTE ( P <0.0001). Conclusions: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia.

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Abstract 175: Performance of a Multilocus Genetic Risk Score Derived from Top Signals in the Cardiogram+C4d Consortium in Predicting Incident Coronary Disease in the Atherosclerosis Risk in Communities Study

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a175 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Themistocles L Assimes ◽

Benjamin Goldstein ◽

Keyword(s):

Risk Prediction ◽

Risk Score ◽

Genetic Risk ◽

Association Studies ◽

Genetic Risk Score ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Genotype Information ◽

Atherosclerosis Risk

Genome wide association studies (GWAS) to date have identified 30 CAD susceptibility loci but the ability to use this information to improve risk prediction remains limited. A meta-analysis of the GWAS and Cardio Metabochip data produced by the CARDIoGRAM+C4D consortium representing 63,253 cases and 126,820 controls has identified 1885 SNPs passing a False Discovery Rate (FDR) threshold of 0.5%. We hypothesized that an expanded multi locus genetic risk score (GRS) incorporating genotype information at all loci below an FDR of 0.5% would perform better than a GRS restricted to 42 loci reaching genome wide significance and tested this hypothesis in subjects of European ancestry participating in the Atherosclerosis Risk in the Community (ARIC) study. Models testing the GRS were either minimally (age and sex) or fully adjusted for traditional risk factors (TRFs). The Figure shows the hazard ratio (HZ) and 95% CI for incident events comparing each quintile of GRS to the middle quintile. The GRS including genotype information at all loci with an FDR of 0.5% noticeably improves risk prediction over the GRS restricted to genome wide significant loci in both the minimally and fully adjusted models based on several metrics including i) HR per GRS quintile, ii) the HR per SD of the GRS, and iii) the logistic regression pseudo R2, and iv) the c statistic. The HR per GRS quintile and per SD of GRS were all lower in the fully adjusted models compared to the respective minimally adjusted models but the reduction of the HR was more striking for the models that tested the more expansive GRS. These findings suggest that a larger proportion of novel GWAS CAD loci are mediating their effects through TRFs. While these findings demonstrate some progress in risk prediction using GWAS loci, both the limited and the expanded GRS continues to explain a relatively small proportion of the overall variance compared to TRF. Thus, the clinical utility of a CAD GRS remains to be determined.

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Abstract P258: Traditional Risk Factors and a Genetic Risk Score Are Associated with Age of First Acute Coronary Syndrome

Circulation ◽

10.1161/circ.129.suppl_1.p258 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Christopher Labos ◽

Leo Rui Wang ◽

Louise Pilote ◽

Peter Bogaty ◽

James M Brophy ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Acute Coronary Syndrome ◽

Risk Score ◽

Genetic Risk ◽

Association Studies ◽

Genetic Risk Score ◽

Genome Wide Association Studies ◽

Coronary Syndrome ◽

Traditional Risk Factors

Background: Early onset myocardial infarction (MI) is frequently attributed to genetic factors that may accelerate the atherosclerotic process. However, early MI may also occur due to a high burden of traditional risk factors. We sought to examine the association between traditional risk factors as well as a genetic risk score on the age of a first acute coronary syndrome (ACS). Methods and Results: We included 460 participants (mean age 59 +/- 12 years, 22.4% female) with a first ACS enrolled in the Recurrence and Inflammation in the Acute Coronary Syndromes (RISCA) cohort. Participants were genotyped for 30 single nucleotide polymorphisms identified from prior myocardial infarction genome-wide association studies to construct a multilocus genetic risk score (GRS). Linear regression models were fit to estimate the association between traditional risk factors (TRFs) and the GRS with age of first ACS. Several TRFs were significantly associated with earlier age of first ACS (all β coefficients in years; p<0.05 for all) : male sex [β=-6.9 (95%CI -9.7,-4.1)], current cigarette smoking [β=-8.1 (95% confidence interval [CI] -10.0, -6.1)], overweight (BMI>25) [β=-2.6 (95%CI -4.8, -0.3)] and obesity (BMI>30) [β=-5.24 (95%CI -7.9, -2.6)]. Use of hormone replacement therapy [β=-4.3 (95%CI -8.4, -0.3) ] and aspirin use were also associated with age of first ACS [β=3.7 (95%CI 0.3, 7.0)]. After multivariable adjustment for TRFs, a one standard deviation increment in the GRS was associated with a 1.0 (95%CI 0.1-2.0) year earlier age of first ACS. Conclusion: Among individuals with a first ACS, a GRS composed of 30 SNPs is associated with a younger age of presentation. Although common genetic predisposition modestly contributes to earlier ACS, a heavy burden of traditional risk factors is strongly associated with markedly earlier ACS.

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The overlap of genetic susceptibility to schizophrenia and cardiometabolic disease can be used to identify metabolically different groups of individuals

Scientific Reports ◽

10.1038/s41598-020-79964-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rona J. Strawbridge ◽

Keira J. A. Johnston ◽

Mark E. S. Bailey ◽

Damiano Baldassarre ◽

Breda Cullen ◽

...

Keyword(s):

Bipolar Disorder ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

European Ancestry ◽

Cardiometabolic Disease ◽

Metabolic Profiles ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Major Depressive ◽

Increased Risk

AbstractUnderstanding why individuals with severe mental illness (Schizophrenia, Bipolar Disorder and Major Depressive Disorder) have increased risk of cardiometabolic disease (including obesity, type 2 diabetes and cardiovascular disease), and identifying those at highest risk of cardiometabolic disease are important priority areas for researchers. For individuals with European ancestry we explored whether genetic variation could identify sub-groups with different metabolic profiles. Loci associated with schizophrenia, bipolar disorder and major depressive disorder from previous genome-wide association studies and loci that were also implicated in cardiometabolic processes and diseases were selected. In the IMPROVE study (a high cardiovascular risk sample) and UK Biobank (general population sample) multidimensional scaling was applied to genetic variants implicated in both psychiatric and cardiometabolic disorders. Visual inspection of the resulting plots used to identify distinct clusters. Differences between these clusters were assessed using chi-squared and Kruskall-Wallis tests. In IMPROVE, genetic loci associated with both schizophrenia and cardiometabolic disease (but not bipolar disorder or major depressive disorder) identified three groups of individuals with distinct metabolic profiles. This grouping was replicated within UK Biobank, with somewhat less distinction between metabolic profiles. This work focused on individuals of European ancestry and is unlikely to apply to more genetically diverse populations. Overall, this study provides proof of concept that common biology underlying mental and physical illness may help to stratify subsets of individuals with different cardiometabolic profiles.

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Mendelian Randomization Focused Analysis of Vitamin D on the Secondary Prevention of Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.032634 ◽

2021 ◽

Author(s):

Yap-Hang Chan ◽

C. Mary Schooling ◽

Jie Zhao ◽

Shiu-Lun Au Yeung ◽

Jo Jo Hai ◽

...

Keyword(s):

Myocardial Infarction ◽

Vitamin D ◽

Ischemic Stroke ◽

Risk Score ◽

Genetic Risk ◽

Odds Ratio ◽

Mendelian Randomization ◽

De Novo ◽

Genetic Risk Score ◽

Ischemic Disease

Background and Purpose: Experimental studies showed vitamin D (Vit-D) could promote vascular regeneration and repair. Prior randomized studies had focused mainly on primary prevention. Whether Vit-D protects against ischemic stroke and myocardial infarction recurrence among subjects with prior ischemic insults was unknown. Here, we dissected through Mendelian randomization any effect of Vit-D on the secondary prevention of recurrent ischemic stroke and myocardial infarction. Methods: Based on a genetic risk score for Vit-D constructed from a derivation cohort sample (n=5331, 45% Vit-D deficient, 89% genotyped) via high-throughput exome-chip screening of 12 prior genome-wide association study–identified genetic variants of Vit-D mechanistic pathways ( rs2060793 , rs4588 , and rs7041 ; F statistic, 73; P <0.001), we performed a focused analysis on prospective recurrence of myocardial infarction (MI) and ischemic stroke in an independent subsample with established ischemic disease (n=441, all with prior first ischemic event; follow-up duration, 41.6±14.3 years) under a 2-sample, individual-data, prospective Mendelian randomization approach. Results: In the ischemic disease subsample, 11.1% (n=49/441) had developed recurrent ischemic stroke or MI and 13.3% (n=58/441) had developed recurrent or de novo ischemic stroke/MI. Kaplan-Meier analyses showed that genetic risk score predicted improved event-free survival from recurrent ischemic stroke or MI (log-rank, 13.0; P =0.001). Cox regression revealed that genetic risk score independently predicted reduced risk of recurrent ischemic stroke or MI combined (hazards ratio, 0.62 [95% CI, 0.48–0.81]; P <0.001), after adjusted for potential confounders. Mendelian randomization supported that Vit-D is causally protective against the primary end points of recurrent ischemic stroke or MI (Wald estimate: odds ratio, 0.55 [95% CI, 0.35–0.81]) and any recurrent or de novo ischemic stroke/MI (odds ratio, 0.64 [95% CI, 0.42–0.91]) and recurrent MI alone (odds ratio, 0.52 [95% CI, 0.30–0.81]). Conclusions: Genetically predicted lowering in Vit-D level is causal for the recurrence of ischemic vascular events in persons with prior ischemic stroke or MI.

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P4455The controversial role of genetics behind premature CAD: a plausible excuse for the young?

European Heart Journal ◽

10.1093/eurheartj/ehz745.0854 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

J Sousa ◽

M Mendonca ◽

A Pereira ◽

F Mendonca ◽

M Neto ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Young Patients ◽

Premature Cad ◽

Artery Disease ◽

Group B

Abstract Introduction The complex interaction between genes and environmental factors contribute to individual-level risk of coronary artery disease (CAD), often resulting in premature CAD. The role for genetic risk scores in premature CAD is still controversial. Objective To evaluate the importance of conventional risk factors and of a genetic risk score in younger and older patients with coronary artery disease Methods From a group of 1619 pts with angiographic documented CAD from the GENEMACOR study, we selected 1276 pts admitted for ACS and analysed them in 2 groups (group A: ≤50 years, n=491 pts, 87.2% male, mean age 44±4.9 and group B: >50 years, n=785 pts, 75.2% male, mean age 57±4.2). Univariate analysis was used to characterize the traits of each group and we used ROC curves and respective AUCs to evaluate the power of genetics in the prediction of CAD, through a Genetic Risk Score (GRS). Results 99.3% of the young patients had at least one modifiable risk factor, 18.4% had 2 modifiable risk factors and 75.2% had 3 or more modifiable risk factors. The pattern of risk factors contributing to CAD were different among groups: family history (A: 27.5%, B: 21.4%, p=0.015) and smoking habits (A: 64.8%, B: 42.9%, p<0.001) were more frequent among patients under 50, and traditional age-linked factors like hypertension (A: 58%, B: 75.7%, p<0.001), diabetes (A: 21.6%, B: 38.6%, p<0.001) were more common in the older group. Acute ST-elevation myocardial infarction was more frequent among the young (A: 55.4%, B: 47.4%, p=0.006), as non-ST clinical presentation was higher among elder patients. Regarding angiographic presentation, single vessel CAD was higher in group A (A: 50.3%, B: 40.9%, p<0.001), while multivessel diasease was higher in group B (A: 33.3%, B: 53.9%, p<0.001). At a mean follow-up of 5 years, older patients had a worst prognosis, registering a higher rate of cardiovascular death (A: 4.1%, B: 8.6%, p=0.002) and higher MACE (A: 26.8%, B: 31%, p=0.128),. Adding the genetic risk score (GRS), we achieved only a slight improvement in the AUC for predicting CAD (0.796->0.805, p=0.0178 and 0.748->0.761, p=0.0007 in patients under and over 50, respectively). Conclusion Coronary artery disease is not all the same, as premature CAD shares a unique and specific pattern of risk factors, clinical presentation, angiographic severity and prognosis. Genetics should not be used as an excuse to justify premature CAD, as there is frequently more than one potentially reversible risk factor present even in young patients and the additive predictive value of GRS is modest.

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