Polygenic risk in Type III hyperlipidaemia and risk of cardiovascular disease: An epidemiological study in UK Biobank and Oxford Biobank. (15th February 2023)

• Record Type: Journal Article
• Authors: Pieri, Kyriaki; Trichia, Eirini; Neville, Matt J.; Taylor, Hannah; Bennett, Derrick; Karpe, Fredrik; Koivula, Robert W.
• Is Part Of: International journal of cardiology. Volume 373(2023)
• Page Start: 72
• Page End: 78
• Publication Date: 2023-02-15
• Subjects: APOE genotype -- Type III hyperlipidaemia -- Polygenic risk -- Dysbetalipoproteinaemia -- NMR metabolomics -- Cardiovascular disease; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2022.11.024
• Languages: English
• ISSNs: 0167-5273

Abstract

Abstract: Background: Type III hyperlipidaemia (T3HL) is characterised by equimolar increases in plasma triglycerides (TG) and cholesterol in <10% of APOE22 carriers conveying high cardiovascular disease (CVD) risk. We investigate the role of a weighted triglyceride-raising polygenic score (TG.PS) precipitating T3HL. Methods: The TG.PS (restricted to genome-wide significance and weighted by published independent effect estimates) was applied to the Oxford Biobank (OBB, n = 6952) and the UK Biobank (UKB, n = 460, 037), to analyse effects on plasma lipid phenotypes. Fasting plasma lipid, lipoprotein biochemistry and NMR lipoprotein profiles were analysed in OBB. CVD prevalence/incidence was examined in UKB. Results: One TG.PS standard-deviation (SD) was associated with 13.0% (95% confidence-interval 12.0–14.0%) greater TG in OBB and 15.2% (15.0–15.4%) in UKB. APOE22 carriers had 19.0% (1.0–39.0%) greater TG in UKB. Males were more susceptible to TG.PS effects (4.0% (2.0–6.0%) greater TG with 1 TG.PS SD in OBB, 1.6% (1.3–1.9%) in UKB) than females. There was no interaction between APOE22 and TG.PS, BMI, sex or age on TG. APOE22 carriers had lower apolipoprotein B (apoB) (OBB; −0.35 (−0.29 to −0.40)g/L, UKB; −0.41 (−0.405 to −0.42)g/L). NMR lipoprotein lipid concentrations were discordant to conventional biochemistry in APOE22 carriers. In APOE22 compared with APOE33, CVD was no more prevalent in similarly hypertriglyceridaemic participants (OR 0.97 95%CI 0.76–1.25), but was less prevalent in normolipidaemia (OR 0.81, 95%CI 0.69–0.95); no differences were observed in CVD incidence. Conclusions: TG.PS confers an additive risk for developing T3HL, that is of comparable effect size to conventional risk factors. The protective effect of APOE22 for prevalent CVD is consistent with lower apoB in APOE22 carriers. Highlights: APOE22 confers a protective effect against cardiovascular disease in normolipidaemia, which is absent in hyperlipidaemia. A triglyceride-raising polygenic score is an additive T3HL risk factor in APOE22 carriers comparable to classic risk factors. Considering polygenic lipid risk in APOE22 may improve prevention, diagnosis and disease management for T3HL.