scholarly journals Polygenic Risk Score Modifies Risk of Coronary Artery Disease Conferred by Low-Density Lipoprotein Cholesterol

2020 ◽  
Author(s):  
Alessandro Bolli ◽  
Paolo Di Domenico ◽  
Roberta Pastorino ◽  
George Busby ◽  
Giordano Bottà
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
Polygenic Risk Score ◽  
Lipid Levels ◽  
Polygenic Risk ◽  
Artery Disease ◽  
Cad Risk ◽  
Blood Lipid Levels

AbstractBackgroundAn individual’s lifetime risk of Coronary Artery Disease (CAD) is determined by a combination of genetic and lifestyle factors. Whilst adherence to a healthy lifestyle can help individuals with high genetic risk reduce their lifetime risk of CAD, the extent to which blood lipid levels affect CAD risk in individuals with varying genetic risk remains unknown. To explore how genetics, blood lipids and CAD risk interact, we derived a novel genome-wide polygenic risk score (PRS) for CAD. We then applied the PRS to individuals from the UK Biobank and divided them into Low PRS (bottom 10 percentiles of PRS distribution), Intermediate PRS (PRS in the 10th-90th percentiles), and High PRS (top 10 percentiles), and further stratified individuals by blood lipid levels.ResultsWe found that the elevated CAD risk conferred by high low-density lipoprotein cholesterol (LDL-C) was modified by the interaction with PRS (P-value interaction: <0.005). Individuals with High PRS and whose LDL-C was Borderline (between 130 and 160 mg/dL) had higher CAD relative risk (HR 3.10; 95% CI, 2.55-3.76) than those at Intermediate PRS whose LDL-C were Very High (>190 mg/dL; HR 2.77; 95% CI, 2.33-3.28). Furthermore, individuals with High PRS but whose lipid levels were below the following thresholds did not have a significantly increased risk for incident CAD: LDL-C <130 mg/dL, total Cholesterol (TC) <200 mg/dL, LDL-C:HDL <2.0 and TC:HDL <3.0. In addition, individuals with Low PRS and Very High LDL-C (>190 mg/dl) did not have increased CAD risk, which was comparable to individuals with Intermediate PRS and Optimal LDL-C (<130 mg/dL).ConclusionsOur results have important implications for the primary prevention of coronary artery disease. Currently, healthy individuals with Borderline LDL-C (130-159 mg/dL) are not considered to be at high risk of CAD. Here we demonstrate that the combination of Borderline LDL-C and High PRS results in CAD relative risk which is greater than individuals without high polygenic risk, but whose LDL-C levels are high enough for statins to be recommended (>190 mg/dL). This analysis therefore demonstrates that PRS can identify a proportion of the population who are at high-risk of CAD but who are invisible to current approaches for assessing CAD risk. Moreover, of perhaps greater significance is the evidence that individuals who have a combination of High PRS and Optimal blood lipid levels do not have greater risk of CAD than individuals without high polygenic risk and the same Optimal blood lipid levels. Our results suggest that high polygenic risk for CAD could be overcome by controlling blood lipid levels. We propose that incorporating PRS into CAD risk assessment early in life could allow individuals at high polygenic risk to benefit from tailored blood lipid guidelines and avoid lifetime exposure to potentially damaging PRS-dependent LDL-C levels.

scholarly journals A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease

2017 ◽  
Vol 26 (12) ◽  
pp. 2364-2376 ◽  
Author(s):  
Eythor Bjornsson ◽  
Hannes Helgason ◽  
Gisli Halldorsson ◽  
Anna Helgadottir ◽  
Arnaldur Gylfason ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Blood Lipid ◽  
Lipid Levels ◽  
Splice Donor ◽  
Artery Disease ◽  
Haptoglobin Gene ◽  
Blood Lipid Levels

scholarly journals Polygenic Hyperlipidemias and Coronary Artery Disease Risk

2019 ◽  
Author(s):  
Pietari Ripatti ◽  
Joel T Rämö ◽  
Nina J Mars ◽  
Sanni Söderlund ◽  
Christian Benner ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Cumulative Exposure ◽  
Risk Scores ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

AbstractBackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.Methods and ResultsWe derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95th percentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).ConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

An Overview of Genetic Factors Influencing Plasma Lipid Levels and Coronary Artery Disease Risk

1999 ◽  
Vol 123 (12) ◽  
pp. 1219-1222 ◽  
Author(s):  
I. Cetin Ozturk ◽  
Anthony A. Killeen
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Disease Risk ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Major Effect ◽  
Genetic Component ◽  
Cholesterol Acyl Transferase ◽  
Artery Disease ◽  
Cad Risk

Abstract Background.—Coronary artery disease (CAD) is a major cause of morbidity and mortality in most Western countries and its origin involves a significant genetic component. Methods.—Genetic and epidemiologic studies have been performed to identify factors that influence the CAD risk in the population. Results.—The primary loci that have been demonstrated to be associated with increased CAD risk owing to genetic mutations include the low-density lipoprotein receptor, apolipoprotein B-100, and lipoprotein(a). Additional implicated loci include lipoprotein lipase, apolipoprotein CII, cholesteryl ester transfer protein, apolipoprotein AI, and lecithin–cholesterol acyl transferase. Conclusions.—Numerous mutations in known genes exert a major effect on CAD risk in some patients. However, in most patients with CAD, the genetic component is believed to be attributable to the aggregate effect of loci that, individually, exert only a minor influence on lipoprotein levels.

scholarly journals Polygenic Hyperlipidemias and Coronary Artery Disease Risk

2020 ◽  
Vol 13 (2) ◽  
Author(s):  
Pietari Ripatti ◽  
Joel T. Rämö ◽  
Nina J. Mars ◽  
Yu Fu ◽  
Jake Lin ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Risk Scores ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank–based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38–3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82–2.94) to 3.78 (95% CI, 3.71–3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18–1.20) mmol/L, ranging from 0.97 (95% CI, 0.94–1.00) to 1.55 (95% CI, 1.48–1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24–1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19–1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16–1.38] for LDL-C and 1.24 [95% CI, 1.13–1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.

scholarly journals Effect of SYTL3-SLC22A3 Variants, Their Haplotypes, and G × E Interactions on Serum Lipid Levels and the Risk of Coronary Artery Disease and Ischaemic Stroke

2021 ◽  
Vol 8 ◽  
Author(s):  
Peng-Fei Zheng ◽  
Rui-Xing Yin ◽  
Xiao-Li Cao ◽  
Wu-Xian Chen ◽  
Jin-Zhen Wu ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Serum Lipid ◽  
Blood Lipid ◽  
Lipid Levels ◽  
Chinese Han ◽  
Han Population ◽  
Southern Chinese ◽  
Artery Disease ◽  
Lipid Parameters

Background: The current study aimed to investigate the effects of synaptotagmin-like 3 (SYTL3) and solute carrier family 22 member 3 (SLC22A3) single nucleotide polymorphisms (SNPs) and gene-environment (G × E) interactions on blood lipid levels as well as the risk of coronary artery disease (CAD) and ischaemic stroke (IS) in the Southern Chinese Han population.Methods: The genetic makeup of 6 SYTL3-SLC22A3 SNPs in 2269 unrelated participants (controls, 755; CAD, 758 and IS, 756) of Chinese Han ethnicity was detected by the next-generation sequencing techniques.Results: The allele and genotype frequencies of the SYTL3 rs2129209 and SLC22A3 rs539298 SNPs were significantly different between the case and control groups. The SLC22A3 rs539298 SNP was correlated with total cholesterol (TC) levels in controls, the rs539298G allele carriers maintained lower TC levels than the rs539298G allele non-carriers. At the same time, the SLC22A3 rs539298 SNP interacted with alcohol consumption reduced the risk of CAD and IS. The SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-C-A and A-T-A-A-C-A haplotypes increased and the A-C-A-A-C-G haplotype reduced the risk of CAD, whereas the SYTL3-SLC22A3 A-C-A-A-A-A, G-T-C-G-A-G and A-T-A-A-C-A haplotypes increased and the A-C-A-A-A-G and A-C-A-A-C-G haplotypes reduced the risk of IS. In addition, several SNPs interacted with alcohol consumption, body mass index ≥ 24 kg/m2 and cigarette smoking to affect serum lipid parameters such as triglyceride, high-density lipoprotein cholesterol, TC, and apolipoprotein A1 levels.Conclusions: Several SYTL3-SLC22A3 variants, especially the rs539298 SNP, several haplotypes, and G × E interactions, were related to blood lipid parameters and the risk of CAD and IS in the Southern Chinese Han population.

scholarly journals Validation of genome-wide polygenic risk scores for coronary artery disease in French Canadians

2019 ◽  
Author(s):  
Florian Wünnemann ◽  
Ken Sin Lo ◽  
Alexandra Langford-Avelar ◽  
David Busseuil ◽  
Marie-Pierre Dubé ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
French Canadian ◽  
French Canadians ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

AbstractCoronary artery disease (CAD) represents one of the leading causes of morbidity and mortality worldwide. Given the healthcare risks and societal impacts associated with CAD, their clinical management would benefit from improved prevention and prediction tools. Polygenic risk scores (PRS) based on an individual’s genome sequence are emerging as potentially powerful biomarkers to predict the risk to develop CAD. Two recently derived genome-wide PRS have shown high specificity and sensitivity to identify CAD cases in European-ancestry participants from the UK Biobank. However, validation of the PRS predictive power and transferability in other populations is now required to support their clinical utility. We calculated both PRS (GPSCAD and metaGRSCAD) in French-Canadian individuals from three cohorts totaling 3639 prevalent CAD cases and 7382 controls, and tested their power to predict prevalent, incident and recurrent CAD. We also estimated the impact of the founder French-Canadian familial hypercholesterolemia deletion (LDLR delta > 15kb deletion) on CAD risk in one of these cohorts and used this estimate to calibrate the impact of the PRS. Our results confirm the ability of both PRS to predict prevalent CAD comparable to the original reports (area under the curve (AUC) = 0.72-0.84). Furthermore, the PRS identified about 6-7% of individuals at CAD risk similar to carriers of the LDLR delta > 15kb mutation, consistent with previous estimates. However, the PRS did not perform as well in predicting incident (AUC= 0.56 - 0.60) or recurrent (AUC= 0.56 - 0.60) CAD. This result suggests that additional work is warranted to better understand how ascertainment biases and study design impact PRS for CAD. Collectively, our results confirm that novel, genome-wide PRS are able to predict CAD in French-Canadians; with further improvements, this is likely to pave the way towards more targeted strategies to predict and prevent CAD-related adverse events.

scholarly journals Prevalence and trends of coronary artery disease risk factors and their effect on age of diagnosis in patients with established coronary artery disease: Tehran Heart Center (2005–2015)

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kaveh Hosseini ◽  
Seyedeh Hamideh Mortazavi ◽  
Saeed Sadeghian ◽  
Aryan Ayati ◽  
Mahdi Nalini ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Density Lipoprotein ◽  
Increasing Trend ◽  
Age Of Diagnosis ◽  
Heart Center ◽  
Artery Disease ◽  
Cad Risk ◽  
Opium Use

Abstract Background Coronary artery disease (CAD) is a universal public health challenge, more prominently so in the low- and middle-income countries. In this study, we aimed to determine prevalence and trends of CAD risk factors in patients with documented CAD and to determine their effects on the age of CAD diagnosis. Materials and methods We conducted a registry-based, serial cross-sectional study using the coronary angiography data bank of the Tehran Heart Center. Adult patients who had obstructive (> 50% stenosis) CAD were included in the study. The prevalence and 11-year trends of conventional CAD risk factors were analyzed by sex and age, and their adjusted effects on the age of CAD diagnosis were calculated. Results From January 2005 to December 2015, data for 90,094 patients were included in this analysis. A total of 61,684 (68.5%) were men and 28,410 (31.5%) were women. Men were younger at diagnosis than women, with a mean age of 60.1 in men and 63.2 in women (p < 0.001), and had fewer risk factors at the time of diagnosis. Mean age at diagnosis had an overall increasing trend during the study period. Increasing trend was seen in body-mass index, hypertension prevalence, diabetes mellitus. All lipid profile components (total cholesterol, low-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol) decreased over time. Of particular interest, opium consumption was associated with 2.2 year earlier age of CAD diagnosis. Conclusion The major results of this study (lower age of CAD diagnosis in men, lower age of diagnosis associated with most risk factors, and lower prevalence of serum lipids over time) were expected. A prominent finding of this study is confirming opium use was associated with a much younger age of CAD onset, even after adjusting for all other risk factors. In addition to recommendations for control of the traditional risk factors, spreading information about the potential adverse effect of opium use, which has only recently been associated with higher risk of CAD, may be necessary.

scholarly journals Unique and Varied Contributions of Traditional CVD Risk Factors: A Systematic Literature Review of CAD Risk Factors in China

2013 ◽  
Vol 7 ◽  
pp. CMC.S10225 ◽  
Author(s):  
Joanne Foody ◽  
Yong Huo ◽  
Linong Ji ◽  
Dong Zhao ◽  
Dylan Boyd ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Real World ◽  
Odds Ratio ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

This study is the first systematic review of risk factors for stroke in China and supports the importance of current public health initiatives to manage the risk factors appropriately to reduce risk of stroke in high risk patients. Additionally, this study has been co-authored by prominent Chinese and US physicians and researchers with expertise in cardiovascular disease, neurologic disorders, epidemiology, and real world data. While there have been several systematic reviews of real world associations of risk factors for coronary artery disease, none focus specifically on the population of China, where there is growing evidence that such risk factors are poorly treated or uncontrolled, especially in rural areas. Background To better understand the impact of traditional cardiovascular risk factors on risk of coronary artery disease (CAD) in China, a systematic review of all Chinese observational studies published in either English or Chinese in MEDLINE and EMBASE over the last 5 years was performed and the association between any of 5 traditional risk factors (ie, hypertension, diabetes, elevated lipid levels, obesity, and smoking) and the risk of CAD was studied. Methods and Results The study found a consistent relationship between lipid levels and CAD. Higher low-density lipoprotein cholesterol values were associated with greater risk of CAD, with an odds ratio as high as 3.31. Other factors found to be significant contributors to the risk of CAD included hypertension (crude odds ratio range of 1.40-5.11), diabetes (1.50-5.97), and smoking (1.37-5.19). An association between obesity and CAD in China was observed, but the evidence supporting this was considered weak due to the paucity of studies found as part of this review. Conclusions This review provides a systematic summary of CAD risk factors in China and demonstrates the important differences that exist in CAD risk factors between countries and regions. Approaches to reduce CAD globally must take into account the unique risk factors that drive CAD in each country and region as is demonstrated by these findings.

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