Optimal blood lipid levels counterbalance high polygenic risk of coronary artery disease in 130 000 individuals. (25th November 2020)

• Record Type: Journal Article
• Authors: Botta, G; Bolli, A; Di Domenico, P
• Is Part Of: European heart journal. Volume 41:(2020)Supplement 2
• Publication Date: 2020-11-25
• Subjects: Risk Factors and Prevention - Epidemiology; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/ehjci/ehaa946.2808
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background: Coronary artery disease (CAD) is a complex multifactorial disease leading cause of morbidity and mortality worldwide. Identifying individuals at high risk is crucial to guide life-style and therapeutics interventions. Polygenic Risk Score (PRS) is a weighted sum of common genetic variants that showed to be able to identify a population at greater than threefold risk of CAD compared to the average. Notably, individuals at high genetic risk who adhere to a healthy lifestyle displayed between two and three-fold relative risk reduction, compared to individuals with a poor lifestyle. Despite such evidences, a systematic assessment of the interplay between PRS and CAD risk factors such as blood lipid levels in contributing to the overall CAD risk is still lacking. Methods: We analysed in more than 130.0000 individuals of the UK Biobank the association of incident CAD with PRS and blood lipids (LDL, TC, HDL, TC:HDL, LDL:HDL) using a Cox Proportional Hazard Model. We defined three populations: i) Carriers: PRS >95%, Reminders: PRS ≤95% and Reference: PRS ≤95% with optimal blood lipid levels. Carriers and Remainders were stratified by blood lipid levels according to international guidelines. We investigated a potential interaction between blood lipids and PRS and assessed the relative increased risk magnitude in Carriers and Reminders for different blood lipid levels. Results: Carriers showed between two and three fold increased risk of incident CAD compared to Reminders at each non-optimal blood lipid level and their ratios. Carriers with LDL between 130 and 160 mg/dL showed higher CAD risk (HR 3.65, 95% CI 2.85–4.63) than Reminders with LDL above 190 mg/dL (HR 2.73, 95% CI 2.18–3.40). Despite that, Carriers displayed non significant increased risk respect to the Reference population for the following blood lipid thresholds: LDL <115 mg/dL, TC <200 mg/dL, HDL >70 mg/dL, LDL:HDL <2.0 and TC:HDL <3.5. The association between LDL cholesterol and CAD was modified by the PRS due to significant interaction (P-value <0.005). The magnitude of increased CAD risk by LDL was higher in Carriers (HR 1.64 95% CI 1.45–1.86 per LDL level) compared to Reminders (HR 1.40, 95% CI 1.34–1.46 per LDL level). Conclusion: Using the largest prospective genotyped cohort available to date, we identified for the first time a significant interaction between LDL and genetics in determining CAD incidence. This result have deep implications in a CAD primary prevention perspective. For example individuals with high PRS and borderline-high LDL levels (130–159 mg/dL) are not currently considered to be at elevated risk, despite having higher CAD risk than Remainders with statin-recommended LDL level (>190 mg/dL). Finally, the evidence that optimal lipid levels counterbalance high genetic risk opens new scenarios in the research of targeted risk reduction in the era of precision medicine. Funding Acknowledgement: Type of funding source: Public grant(s) – EU funding. Main funding source(s): EIT Health