Abstract P457: Age Dependence of Genetic Risk Scores in Relation to Coronary Artery Disease

Background: Coronary artery disease (CAD) is an age-related multi-factorial disease with a high public health burden. Genetic loci for CAD have been discovered and collectively predict CAD risk independent of traditional risk factors. It remains unclear whether age modifies the genetic predisposition to CAD. Methods: A total of 173,315 Caucasian subjects from the UK Biobank were included in this study, including 26,472 CAD patients with age of onset ranging from 32 to 78 years old, and 146,843 control subjects > 60 years old without CAD. CAD diagnosis was extracted from in-patient Hospital Episode Statistics (HES) and National Death Registry based on ICD-10 and OPCS-4 codes. CAD genetic risk score (GRS) was calculated based on the 161 known CAD loci. Sub-GRSs for body mass index (BMI, 16 loci), blood pressure (BP, 26 loci) and lipids (17 loci) were constructed to examine the genetic risk for CAD from certain intermediate trait. The CAD GRSs among onset age groups were compared to the controls using linear regression models, controlling for sex, BMI, creatinine, c-reactive protein, high density lipoprotein, low density lipoprotein, triglyceride, diabetes, heart failure history, hypertension and smoking status. The sub-GRSs were compared using the same models, excluding sub-GRS specific intermediate traits. Interactions of age groups and GRSs were tested using logistic regression models for CAD status, controlling for the same variables described above. Association analyses of each GRS were performed within each category of CAD age at onset comparing to controls. Results: Compared to the controls, the mean CAD GRS in CAD patients with age of onset ≤ 50 years was 0.58 standard deviations (SD) higher (95% CI 0.53-0.63), followed by CAD age of onset between 50 and 60 years (0.50 SD higher, 95% CI 0.48-0.52), between 60 and 70 years (0.35 SD higher, 95% CI 0.33-0.37), and > 70 years (0.25 SD higher, 95% CI 0.21-0.29). The sub-GRSs showed the similar trend. Age of onset stratified analysis revealed a significant CAD GRS-age interaction (p<0.001) on CAD risk where genetic effect is stronger among those early onset CAD patients - the odds ratios (OR) per CAD GRS SD among subjects with CAD onset age ≤ 50, 50 to 60, 60 to 70, > 70 years were 1.80 (95% CI 1.71-1.89), 1.66 (95% CI 1.62-1.70), 1.44 (1.41-1.47), 1.29 (95%CI 1.24-1.35), respectively. Among the three sub-GRSs, significant GRS-age interactions were observed for BP sub-GRS and lipids sub-GRS but not BMI sub-GRS. Conclusion: The observed gene-age interaction indicates that the genetic susceptibility for CAD decreases for older subjects. The contribution of the CAD GRS to CAD risk is almost 64% lower in those developing CAD at age > 70 years compared to those ≤ 50 years. Future considerations and applications of CAD genetic risk in precision medicine needs to include age of onset to accurately evaluate the genetic contribution.

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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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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)

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02293-y ◽

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.

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Coronary artery disease, genetic risk and the metabolome in young individuals

Wellcome Open Research ◽

10.12688/wellcomeopenres.14788.1 ◽

2018 ◽

Vol 3 ◽

pp. 114 ◽

Cited By ~ 5

Author(s):

Thomas Battram ◽

Luke Hoskins ◽

David A. Hughes ◽

Johannes Kettunen ◽

Susan M. Ring ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Genetic Variants ◽

Genetic Risk ◽

Association Studies ◽

Genetic Risk Score ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Artery Disease

Background: Genome-wide association studies have identified genetic variants associated with coronary artery disease (CAD) in adults – the leading cause of death worldwide. It often occurs later in life, but variants may impact CAD-relevant phenotypes early and throughout the life-course. Cohorts with longitudinal and genetic data on thousands of individuals are letting us explore the antecedents of this adult disease. Methods: 149 metabolites, with a focus on the lipidome, measured using nuclear magnetic resonance (1H-NMR) spectroscopy, and genotype data were available from 5,905 individuals at ages 7, 15, and 17 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Linear regression was used to assess the association between the metabolites and an adult-derived genetic risk score (GRS) of CAD comprising 146 variants. Individual variant-metabolite associations were also examined. Results: The CAD-GRS associated with 118 of 149 metabolites (false discovery rate [FDR] < 0.05), the strongest associations being with low-density lipoprotein (LDL) and atherogenic non-LDL subgroups. Nine of 146 variants in the GRS associated with one or more metabolites (FDR < 0.05). Seven of these are within lipid loci: rs11591147 PCSK9, rs12149545 HERPUD1-CETP, rs17091891 LPL, rs515135 APOB, rs602633 CELSR2-PSRC1, rs651821 APOA5, rs7412 APOE-APOC1. All associated with metabolites in the LDL or atherogenic non-LDL subgroups or both including aggregate cholesterol measures. The other two variants identified were rs112635299 SERPINA1 and rs2519093 ABO. Conclusions: Genetic variants that influence CAD risk in adults are associated with large perturbations in metabolite levels in individuals as young as seven. The variants identified are mostly within lipid-related loci and the metabolites they associated with are primarily linked to lipoproteins. This knowledge could allow for preventative measures, such as increased monitoring of at-risk individuals and perhaps treatment earlier in life, to be taken years before any symptoms of the disease arise.

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The Atherogenic Index of Plasma: A Powerful and Reliable Predictor for Coronary Artery Disease in Patients With Type 2 Diabetes

Angiology ◽

10.1177/00033197211012129 ◽

2021 ◽

pp. 000331972110121

Author(s):

Kuo Zhou ◽

Zheng Qin ◽

Jinfan Tian ◽

Kongyong Cui ◽

Yunfeng Yan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Atherogenic Index ◽

Atherogenic Index Of Plasma ◽

Artery Disease ◽

Cad Risk

We evaluated the predictive power of the atherogenic index of plasma (AIP) for coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). A total of 3278 patients who underwent coronary angiography were consecutively enrolled, including 2052 patients with CAD and 1226 patients with T2DM but without CAD. Patients in the CAD group had higher levels of triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, AIP and a lower level of high-density lipoprotein cholesterol (HDL-C). In correlation analyses, AIP correlated positively with body mass index, log (homeostasis model assessment of insulin resistance), TG, remnant lipoprotein cholesterol, non–HDL-C, but negatively with age and HDL-C. Multivariate logistic regression analyses demonstrated that AIP was an independent risk factor for CAD in diabetic patients and was validated by multiple models. Furthermore, the ORs for CAD risk were raised with increasing AIP quartiles; ORs of AIP quartiles Q2–Q4 compared with Q1 were 1.56, 1.70, and 2.22, respectively ( Ps < .001), which suggested AIP was the lipid parameter that most strongly associated with incident CAD. In conclusion, AIP is a powerful and reliable biomarker for predicting CAD risk beyond individual lipid profiles in patients with T2DM.

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Polygenic risk for coronary artery disease in the Scottish and English population

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02398-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chuhua Yang ◽

Fabian Starnecker ◽

Shichao Pang ◽

Zhifen Chen ◽

Ulrich Güldener ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Individual Risk ◽

Risk Alleles ◽

Genome Wide ◽

Artery Disease ◽

Cad Risk

Abstract Background Epidemiological studies have repeatedly observed a markedly higher risk for coronary artery disease (CAD) in Scotland as compared to England. Up to now, it is unclear whether environmental or genetic factors might explain this phenomenon. Methods Using UK Biobank (UKB) data, we assessed CAD risk, based on the Framingham risk score (FRS) and common genetic variants, to explore the respective contribution to CAD prevalence in Scotland (n = 31,963) and England (n = 317,889). We calculated FRS based on sex, age, body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), antihypertensive medication, smoking status, and diabetes. We determined the allele frequency of published genome-wide significant risk CAD alleles and a weighted genetic risk score (wGRS) for quantifying genetic CAD risk. Results Prevalence of CAD was 16% higher in Scotland as compared to England (8.98% vs. 7.68%, P < 0.001). However, the FRS only predicted a marginally higher CAD risk (less than 1%) in Scotland (12.5 ± 10.5 vs.12.6 ± 10.6, P = 0.03). Likewise, the overall number of genome-wide significant variants affecting CAD risk (157.6 ± 7.7 and 157.5 ± 7.7; P = 0.12) and a wGRS for CAD (2.49 ± 0.25 in both populations, P = 0.14) were remarkably similar in the English and Scottish population. Interestingly, we observed substantial differences in the allele frequencies of individual risk variants. Of the previously described 163 genome-wide significant variants studied here, 35 variants had higher frequencies in Scotland, whereas 37 had higher frequencies in England (P < 0.001 each). Conclusions Neither the traditional risk factors included in the FRS nor a genetic risk score (GRS) based on established common risk alleles explained the higher CAD prevalence in Scotland. However, we observed marked differences in the distribution of individual risk alleles, which emphasizes that even geographically and ethnically closely related populations may display relevant differences in the genetic architecture of a common disease.

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Coronary artery disease, genetic risk and the metabolome in young individuals

Wellcome Open Research ◽

10.12688/wellcomeopenres.14788.2 ◽

2019 ◽

Vol 3 ◽

pp. 114 ◽

Cited By ~ 3

Author(s):

Thomas Battram ◽

Luke Hoskins ◽

David A. Hughes ◽

Johannes Kettunen ◽

Susan M. Ring ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Genetic Variants ◽

Genetic Risk ◽

Association Studies ◽

Genetic Risk Score ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Artery Disease

Background: Genome-wide association studies have identified genetic variants associated with coronary artery disease (CAD) in adults – the leading cause of death worldwide. It often occurs later in life, but variants may impact CAD-relevant phenotypes early and throughout the life-course. Cohorts with longitudinal and genetic data on thousands of individuals are letting us explore the antecedents of this adult disease. Methods: 148 metabolites, with a focus on the lipidome, measured using nuclear magnetic resonance (1H-NMR) spectroscopy, and genotype data were available from 5,907 individuals at ages 7, 15, and 17 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Linear regression was used to assess the association between the metabolites and an adult-derived genetic risk score (GRS) of CAD comprising 146 variants. Individual variant-metabolite associations were also examined. Results: The CAD-GRS associated with 118 of 148 metabolites (false discovery rate [FDR] < 0.05), the strongest associations being with low-density lipoprotein (LDL) and atherogenic non-LDL subgroups. Nine of 146 variants in the GRS associated with one or more metabolites (FDR < 0.05). Seven of these are within lipid loci: rs11591147 PCSK9, rs12149545 HERPUD1-CETP, rs17091891 LPL, rs515135 APOB, rs602633 CELSR2-PSRC1, rs651821 APOA5, rs7412 APOE-APOC1. All associated with metabolites in the LDL or atherogenic non-LDL subgroups or both including aggregate cholesterol measures. The other two variants identified were rs112635299 SERPINA1 and rs2519093 ABO. Conclusions: Genetic variants that influence CAD risk in adults are associated with large perturbations in metabolite levels in individuals as young as seven. The variants identified are mostly within lipid-related loci and the metabolites they associated with are primarily linked to lipoproteins. Along with further research, this knowledge could allow for preventative measures, such as increased monitoring of at-risk individuals and perhaps treatment earlier in life, to be taken years before any symptoms of the disease arise.

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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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A study of associations between CUBN, HNF1A, and LIPC gene polymorphisms and coronary artery disease

Scientific Reports ◽

10.1038/s41598-020-73048-6 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Han Sung Park ◽

In Jai Kim ◽

Eun Gyo Kim ◽

Chang Soo Ryu ◽

Jeong Yong Lee ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Gene Polymorphisms ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Genotype Combination ◽

Whole Exome ◽

Elevated Cholesterol ◽

Artery Disease ◽

Cad Risk

Abstract The aim of this study was to identify novel genetic markers related to coronary artery disease (CAD) using a whole-exome sequencing (WES) approach and determine any associations between the selected gene polymorphisms and CAD prevalence. CUBN, HNF1A and LIPC gene polymorphisms related to CAD susceptibility were identified using WES screening. Possible associations between the five gene polymorphisms and CAD susceptibility were examined in 452 CAD patients and 421 control subjects. Multivariate logistic regression analyses indicated that the CUBN rs2291521GA and HNF1A rs55783344CT genotypes were associated with CAD (GG vs. GA; adjusted odds ratio [AOR] = 1.530; 95% confidence interval [CI] 1.113–2.103; P = 0.002 and CC vs. CT; AOR = 1.512; 95% CI 1.119–2.045; P = 0.007, respectively). The CUBN rs2291521GA and HNF1A rs55783344CT genotype combinations exhibited a stronger association with CAD risk (AOR = 2.622; 95% CI 1.518–4.526; P = 0.001). Gene-environment combinatorial analyses indicated that the CUBN rs2291521GA, HNF1A rs55783344CT, and LIPC rs17269397AA genotype combination and several clinical factors (fasting blood sugar (FBS), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels) were associated with increased CAD risk. The CUBN rs2291521GA, HNF1A rs55783344CT, and LIPC rs17269397AA genotypes in conjunction with abnormally elevated cholesterol levels increase the risk of developing CAD. This exploratory study suggests that polymorphisms in the CUBN, HNF1A, and LIPC genes can be useful biomarkers for CAD diagnosis and treatment.

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Single-nucleotide polymorphism rs731384 is associated with plasma lipid levels and the risk of coronary artery disease in Chinese populations

Bioscience Reports ◽

10.1042/bsr20181502 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 1

Author(s):

Chenhui Zhao ◽

Mingyue Ji ◽

Jing Zhang ◽

Qiaowei Jia ◽

Jieyin Liu ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Protective Factor ◽

Plasma Lipids ◽

Venous Blood ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Environment Interaction ◽

Artery Disease ◽

Cad Risk

Aims: To investigate the relationship between the miR-130a polymorphism rs731384 and coronary artery disease (CAD) and to further explore the molecular mechanism of the pathogenesis of CAD, an observational single-center study was conducted. Method: A total of 876 subjects were recruited in the present study. Four milliliters of venous blood was drawn after 12 h of fasting to perform biochemical assays. CAD patients and controls were distinguished by coronary angiography. Rs731384 was genotyped on the Agena MassARRAY system according to the manufacturer’s user guide. Statistical analysis was conducted using SPSS 16.0 software. Results: The study found that the plasma levels of total cholesterol (TC) (P=0.006), low-density lipoprotein cholesterol (LDL-C) (P=0.030), apolipoprotein A (ApoA) (P=0.038), and apolipoprotein B (ApoB) (P=0.022) distributed differently in patients with various alleles. Additionally, the AA genotype of rs731384 was found to be a protective factor against CAD in a recessive model (AA:AG+GG, odds ratio (OR) = 0.408, 95% confidence interval (95% CI) = 0.171–0.973, P=0.043). A significant association was found between the gene–environment interaction and CAD risk. The AA genotype along with high-density lipoprotein cholesterol (HDL-C) level ≥ 1.325 mmol/l significantly decreased the CAD risk (AA:AG+GG, OR = 0.117, 95% CI = 0.023–0.588, P=0.009). Conclusion: The mutant AA genotype of rs731384 seems to be a protective factor against CAD, and rs731384 plays an important role in the human metabolism of plasma lipids.

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

10.1101/2020.03.01.20029454 ◽

2020 ◽

Cited By ~ 1

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.

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