Coronary artery disease risk and lipidomic profiles are similar in familial and population-ascertained hyperlipidemias

AbstractAims: To characterize and compare coronary artery disease (CAD) risk and detailed lipidomic profiles of individuals with familial and population-ascertained hyperlipidemias.Methods and Results: We determined incident CAD risk for 760 members of 66 hyperlipidemic families (≥ 2 first degree relatives with the same hyperlipidemia) and 19,644 Finnish FINRISK population study participants. We also quantified 151 lipid species in plasma or serum samples from 550 members of 73 hyperlipidemic pedigrees and 897 FINRISK participants using a mass spectrometric shotgun lipidomics platform. Hyperlipidemias (LDL-C or triacylglycerides over 90th population percentile) were associated with increased CAD risk (high LDL-C: HR 1.74, 95% CI 1.48–2.04; high triacylglycerides: HR 1.38, 95% CI 1.09–1.74) and the risk estimates were very similar between the family and population samples. High LDL-C was associated with altered levels of 105 lipid species in families (p-value range 0.033–7.3*10−20 at 5% false discovery rate) and 51 species in the population samples (p-value range 0.017–6.8*10−21). Hypertriglyceridemia was associated with altered levels of 117 lipid species in families (p-value range 0.035–1.8*10−49) and 119 species in the population sample (p-value range 0.038–2.3*10−56). The lipidomics profiles of hyperlipidemias were highly similar in families and population samples.Conclusion: We identified distinct lipidomic profiles associated with high LDL-C and triacylglyceride levels. CAD risk, lipidomic profiles and genetic profiles are highly similar between familial and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms. Our results do not support different screening and treatment for such hyperlipidemias.

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Polygenic Hyperlipidemias and Coronary Artery Disease Risk

10.1101/735167 ◽

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.

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

Archives of Pathology & Laboratory Medicine ◽

10.5858/1999-123-1219-aoogfi ◽

1999 ◽

Vol 123 (12) ◽

pp. 1219-1222 ◽

Cited By ~ 1

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.

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Polygenic Hyperlipidemias and Coronary Artery Disease Risk

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.119.002725 ◽

2020 ◽

Vol 13 (2) ◽

Cited By ~ 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.

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Breast Arterial Calcifications: Reporting Preferences and Impact on Screening for Coronary Artery Disease

Journal of Breast Imaging ◽

10.1093/jbi/wbab076 ◽

2021 ◽

Author(s):

Kaitlin M Zaki-Metias ◽

Jeffrey J MacLean ◽

Paul A Mergo ◽

Barakat Ogunde ◽

Mohammed Al-Hameed ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Primary Care Physicians ◽

Disease Risk ◽

The Body ◽

P Value ◽

Chi Square ◽

Institutional Review ◽

Artery Disease ◽

Associated Risk Factors

Abstract Objective Breast arterial calcifications (BAC) have been shown to correlate with measures of coronary artery disease risk stratification, although reporting of BAC is optional by BI-RADS guidelines. The purpose of this study is to determine referring provider preferences in BAC reporting on mammography reports and if such reporting has any impact on patient management. Methods This study was approved by the local institutional review board. A voluntary eight-question survey regarding the preferences and outcomes of BAC reporting on mammography was distributed to 1085 primary care physicians, obstetrics and gynecologists, medical oncologists, and breast and general surgeons in our health system via a secure online platform. Data analysis including Pearson chi-square was performed with a P-value of <0.05 for significance. Results A response rate of 19.1% (207/1085) was attained, with 21/207 (10.1%) of respondents indicating they do not routinely order mammograms excluded from further analysis. A total of 62.4% (116/186) of ordering physicians indicated a preference for reporting of BAC in both the body and impression of the radiology report, with 82.3% (153/186) of respondents placing importance on the quantity of atherosclerotic calcifications. Most participants (79.6%, 148/186) reported that the presence of BAC would prompt further investigation for coronary artery disease and associated risk factors. Conclusion The majority of responding physicians indicated a preference for detailed reporting of BAC and that such reporting would impact patient care. Understanding referring provider preferences regarding ancillary findings of BAC will allow for improved communication and value in mammography.

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Association of Circulating microRNAs with Coronary Artery Disease and Usefulness for Reclassification of Healthy Individuals: The REGICOR Study

Journal of Clinical Medicine ◽

10.3390/jcm9051402 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1402 ◽

Cited By ~ 2

Author(s):

Irene R. Dégano ◽

Anna Camps-Vilaró ◽

Isaac Subirana ◽

Nadia García-Mateo ◽

Pilar Cidad ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Cox Regression ◽

Low Density Lipoproteins ◽

Microrna Expression ◽

Circulating Microrna ◽

Low Density ◽

Serum Samples ◽

Artery Disease ◽

Cad Risk

Risk prediction tools cannot identify most individuals at high coronary artery disease (CAD) risk. Oxidized low-density lipoproteins (oxLDLs) and microRNAs are actively involved in atherosclerosis. Our aim was to examine the association of CAD and oxLDLs-induced microRNAs, and to assess the microRNAs predictive capacity of future CAD events. Human endothelial and vascular smooth muscle cells were treated with oxidized/native low-density lipoproteins, and microRNA expression was analyzed. Differentially expressed and CAD-related miRNAs were examined in serum samples from (1) a case-control study with 476 myocardial infarction (MI) patients and 487 controls, and (2) a case-cohort study with 105 incident CAD cases and 455 randomly-selected cohort participants. MicroRNA expression was analyzed with custom OpenArray plates, log rank tests and Cox regression models. Twenty-one microRNAs, two previously undescribed (hsa-miR-193b-5p and hsa-miR-1229-5p), were up- or down-regulated upon cell treatment with oxLDLs. One of the 21, hsa-miR-122-5p, was also upregulated in MI cases (fold change = 4.85). Of the 28 CAD-related microRNAs tested, 11 were upregulated in MI cases-1 previously undescribed (hsa-miR-16-5p)-, and 1/11 was also associated with CAD incidence (adjusted hazard ratio = 0.55 (0.35–0.88)) and improved CAD risk reclassification, hsa-miR-143-3p. We identified 2 novel microRNAs modulated by oxLDLs in endothelial cells, 1 novel microRNA upregulated in AMI cases compared to controls, and one circulating microRNA that improved CAD risk classification.

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Abstract 534: A Common Null Allele of LPA is Associated With Lp(a) Levels and Coronary Artery Disease Risk

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.534 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Theodosios Kyriakou ◽

Udo Seedorf ◽

Anuj Goel ◽

Jemma C Hopewell ◽

Robert Clarke ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Null Allele ◽

Disease Risk ◽

Case Control ◽

Control Cohort ◽

Apolipoprotein A ◽

Artery Disease ◽

The Relationship ◽

Cad Risk

Objective: Increased levels of Lp(a) lipoprotein are a highly heritable risk factor for coronary artery disease (CAD). The genetic determinants of Lp(a) levels are mainly due to genetic variation in the apolipoprotein(a) gene (LPA). We have tested the association of a null allele of LPA with Lp(a) levels and CAD risk in a large case-control cohort. We have also examined how null allele genotyping complements apolipoprotein(a) isoform typing to refine the relationship between LPA isoform size and circulating Lp(a) levels. Approach and Results: The LPA null allele (rs41272114) was genotyped in the PROCARDIS case-control cohort (4,073 CAD cases, 4,225 controls). Lp(a) lipoprotein levels were measured in 909 CAD cases and 922 controls; apolipoprotein(a) isoform size was estimated using SDS-agarose gel electrophoresis and a high-throughput qPCR based method. Null carriers are common (null allele frequency 3%) and have significantly lower circulating Lp(a) levels (p=2.1x10-10) and reduced CAD risk (p=0.023) compared to non-carriers. An additive allelic model of apolipoprotein(a) isoform size, refined by null allele genotype and qPCR values, showed a sigmoid relationship with Lp(a) levels with baseline levels for longer isoform alleles and progressively higher levels of Lp(a) for shorter isoform alleles. Conclusions: The LPA null allele (rs41272444) is associated with decreased circulating Lp(a) levels and decreased CAD risk. A joint genomic and isoform analysis revealed details of the relationship between apolipoprotein(a) isoform size and circulating Lp(a) level consistent with a threshold effect on lipoprotein secretion.

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Abstract P148: Sex Differences in the Genetic Predisposition of Coronary Artery Disease

Circulation ◽

10.1161/circ.141.suppl_1.p148 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Yunfeng Huang ◽

Qin Hui ◽

Marta Gwinn ◽

Yijuan Hu ◽

Arshed A Quyyumi ◽

...

Keyword(s):

Coronary Artery Disease ◽

Sex Differences ◽

Coronary Artery ◽

Genetic Risk ◽

P Value ◽

Men And Women ◽

Specific Effects ◽

History Of ◽

Artery Disease ◽

Cad Risk

While coronary artery disease (CAD) is the leading cause of death for both men and women, sex differences in CAD risk are widely observed. Genetic susceptibility for CAD may be modified by sex and contribute to sex disparities in CAD. However, whether such modification exists is not clear given the limited sample size of previous studies. Using the UK Biobank, we constructed a CAD genetic risk score (CAD-GRS) based on 161 known loci, and assessed the sex-specific effect of the CAD-GRS on CAD incidence in ~307,147 men and women of European ancestry without previous history of CAD. During an average follow-up of 6.1 years 9,847 incident CAD events were identified using hospitalization data and the national death registry. To examine if certain intermediate trait contributes more predominantly on sex differences in CAD risk, we constructed three risk factor-based CAD-sub-GRSs after removing pleiotropic SNPs: 1) 26 loci associated with blood pressure (BP) and CAD (BP-sub-GRS); 2) 17 loci associated with lipids and CAD (lipids-sub-GRS); and 3) 16 loci associated with body mass index (BMI) and CAD (BMI-sub-GRS). Sex-specific effects of CAD-sub-GRSs were examined. Cox models were implemented to assess sex-specific genetic effects of CAD adjusted for age, smoking, alcohol drinking, history of hypertension and diabetes, BMI, cholesterol medication, education and SES, and population stratification. To avoid over-adjustment, history of hypertension, cholesterol medication and BMI were not controlled for in the analyses of BP-sub-GRS, lipids-sub-GRS and BMI-sub-GRS, respectively. Both CAD-GRS and CAD-sub-GRSs were categorized using quintiles into “low” (quintile 1), “intermediate” (quintile 2 - 4), and “high” (quintile 5) groups. We observed a strong sex discrepancy in the effect of the overall CAD-GRS on CAD incidence (HR high GRS vs. low GRS = 2.4 (95% CI: 2.2, 2.6) for males vs. HR high GRS vs. low GRS = 1.8 (95% CI: 1.6, 2.0) for females, interaction p-value = 0.002). A similar gene-sex interaction was observed for CAD-sub-GRS driven by BP-associated loci (HR high GRS vs. low GRS = 1.5 (95% CI: 1.4, 1.7) for males vs. HR high GRS vs. low GRS = 1.2 (95% CI: 1.1, 1.3) for females, interaction p-value = 0.0005) but not lipids or BMI-associated loci. The SNP-based analysis revealed significant gene-sex interaction (p=0.0001) at one CAD locus (21q22.11). The lead SNP (rs28451064) is a cis -eQTL for several neighboring genes’ expression ( MRPS6 , SLC5A3 , KCNE2 and AP000318.2 ) in aorta and tibial artery tissues. Previous genome-wide association studies reported significant associations between rs28451064 and bone mineral density, waist-hip ratio as well as pulse pressure. These results suggest that genetic predisposition of CAD based on known loci is stronger in men than in women. Future investigations of genetic risk and mechanism for CAD need to consider sex-specific effects.

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Metabolic Syndrome and Coronary Artery Disease Risk: A Meta-Analysis of Observational Studies

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18041773 ◽

2021 ◽

Vol 18 (4) ◽

pp. 1773

Author(s):

Amal F. Alshammary ◽

Khalid Khalaf Alharbi ◽

Naif Jameel Alshehri ◽

Vishal Vennu ◽

Imran Ali Khan

Keyword(s):

Coronary Artery Disease ◽

Metabolic Syndrome ◽

Coronary Artery ◽

Observational Studies ◽

Web Of Science ◽

Disease Risk ◽

Meta Analysis ◽

Coronary Artery Disease Risk ◽

Artery Disease ◽

Cad Risk

Although numerous studies have described the link between metabolic syndrome (MetS) and Coronary Artery Disease (CAD), no meta-analysis has been carried out on this relationship. Thus, the present study intended to address this limitation. A systematic search was carried out using electronic databases, such as PubMed, CINAHL Plus, Medline, and Web of Science. A sum of 10 studies (n = 9327) was incorporated in the meta-analysis. Compared with non-MetS, MetS was significantly associated with high CAD risk (OR = 4.03, 95% CI = 3.56–4.56). The MetS components were also significantly correlated with high CAD risk (OR = 3.72, 95% CI = 3.22–4.40). The presence of two (OR = 3.93, 95% CI = 2.81–5.49), three (OR = 4.09, 95% CI = 2.85–5.86), four (OR = 4.04, 95% CI = 2.83–5.78), or all five MetS components (OR = 3.92, 95% CI = 3.11–4.93), were significantly associated with a high risk of CAD. MetS and its individual or combined elements were linked with high CAD risk based on contemporary evidence. Thus, the assessment of MetS and its components might help identify people at a higher risk of advancing CAD in the future.

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Association of human platelet alloantigens encoding gene polymorphisms with the risk of Coronary artery disease in Iranian patients

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-01892-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Farideh Malakootikhah ◽

Hossein Naghavi ◽

Negar Firouzabadi ◽

Mohsen Maadani ◽

Massoumeh Shafiei ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Disease Risk ◽

Human Platelet ◽

Univariate Analysis ◽

Iranian Population ◽

Risk Haplotype ◽

Retrospective Case ◽

Artery Disease ◽

Cad Risk

Abstract Background Coronary artery disease (CAD) is characterized by narrowing/ blockade of coronary arteries that is mainly caused by atherosclerotic plaques. Considering the involvement of platelet abnormalities, such as defective aggregation and adhesion, in the cardiovascular-related disorders, genetic variations in human platelet alloantigens (HPA) have been implicated in the CAD susceptibility. Herein, we intended to determine the association of HPA-1 to -6, -9, and -15 biallelic polymorphisms with CAD in an Iranian population. Methods In this retrospective case–control study, 200 CAD subjects and 100 matched healthy individuals were enrolled. DNA samples were isolated from peripheral blood samples and genotyping of HPA polymorphisms was accomplished using polymerase chain reaction-sequence-specific primers. Results The alleles and genotypes of studied HPA polymorphisms were equally distributed among cases and controls and therefore no statistically significant differences were detected. Univariate analysis identified no association of combined haplotypes with CAD risk. However, multivariate analysis showed a positive association of the‌ HPA1b/2a/3b haplotype with CAD after adjustment for some covariates (including BMI, TG, LDL, FBS and blood pressure) that conferred a CAD susceptibility haplotype (P = 0.015; OR = 2.792; 95% CI 1.45–8.59). Conclusions Although alleles, genotypes, and haplotypes of HPA polymorphisms were not associated with CAD risk, HPA1b/2a/3b haplotype was found to be a dependent disease risk haplotype in Iranian population after correcting for confounding factors.

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Predicting coronary artery disease risk in firefighters – a cross-sectional study

F1000Research ◽

10.12688/f1000research.54219.1 ◽

2021 ◽

Vol 10 ◽

pp. 701

Author(s):

Jaron Ras ◽

Lloyd Leach

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Cigarette Smoking ◽

Central Obesity ◽

Disease Risk ◽

Full Time ◽

Cross Sectional ◽

Artery Disease ◽

Cad Risk

Background: Firefighters are placed under severe cardiovascular load in performing active duty and, when carrying various coronary artery disease (CAD) risk factors, firefighters are predisposed to significant morbidity and mortality. Reducing the incidence of these risk factors is paramount. The purpose of this study is to determine the predictors of CAD risk. Methods: This study used a quantitative, cross-sectional and correlational design. The researchers conveniently sampled 124 full-time firefighters from the City of Cape Town Fire and Rescue Service. A researcher-generated questionnaire was used to collect sociodemographic and CAD risk factors information, such as age, gender, ethnicity, family history of CAD, cigarette smoking and physical activity levels, and all research procedures were conducted according to the American College of Sports Medicine guidelines. Data collection took place between September and November 2019. Linear and logistic regression were used to determine the relationship between the various CAD risk factors and the predictors of CAD risk. Results: Age was a significant predictor of hypertension (p <0.01), dyslipidemia (p <0.01), diabetes (p <0.01), obesity (p <0.01) and central obesity (p <0.01). Gender was a significant predictor of obesity, central obesity and cigarette smoking (p <0.05). Waist circumference was a significant predictor of hypertension (p <0.01), dyslipidemia (p <0.01) and diabetes (p <0.05). Conclusion: Age was a significant predictor of various modifiable CAD risk factors, including obesity, in both genders and all ethnicities. Attentive monitoring should be in place as firefighters age, along with behavioural modifications designed to reduce age-related increases in CAD risk factors.

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