Endocrine Abstracts

Background: Type III hyperlipidaemia (T3HL) is characterised by equimolar increases in plasma triglyceride and cholesterol on an APOE2/2 genotype background and conveys a high risk of early-onset cardiovascular disease (CVD). Phenotypic penetrance of T3HL is <10% and precipitated by several endocrine/metabolic disorders such as obesity, diabetes and hypothyroidism. We explored the effect of triglyceride-raising polygenic score precipitating T3HL, in the context of known precipitants and CVD.

Methods: A weighted polygenic score (TG.PS) was developed using 107 independent triglyceride-raising genetic variants identified from GLGC-GWAS. The TG.PS was applied to the Oxford Biobank (OBB, n = 6,952) and the UK Biobank (UKB, n = 460,037) to analyse effects on plasma lipid phenotypes. The relationship between APOE2/2 status and prevalent or incident CVD was examined in UKB.

Results: TG.PS was strongly associated with an increase in triglyceride concentration in OBB and UKB (1 TG.PS SD equalled to +13-15%, P = 5.52×10^-128 (OBB), P < 10^-300 (UKB)). Similarly, APOE2/2 carrier status increased triglycerides by 19% (P = 0.039, UKB). Males were more susceptible to TG.PS effects (interaction-P = 1.44×10^-05 (OBB), interaction-P = 6.40×10^-25 (UKB)). There was no interaction between the APOE2/2 genotype and TG.PS, BMI, sex or age in raising triglycerides. APOE2/2 carriers had lower apoB (P = 5.97×10^-34 (OBB), P < 10^-300(UKB)). In cross-sectional CVD analysis, restricted to males with APOE2/2 and APOE3/3 genotypes, T3HL exhibited no more risk of CVD compared with similarly hypertriglyceridaemic participants (OR 1.08, 95%CI 0.81-1.44, P = 0 .61). However, in normolipidaemia (triglycerides ≤ 3mmol/l), APOE2/2 carriers had less prevalent CVD (OR 0.77, 95%CI 0.62-0.94, P = 0 .01), but no difference in incident CVD (OR 0.91, 95%CI 0.71-1.15, P = 0 .42).

Conclusion: TG.PS confers an additive risk for developing T3HL, of comparable effect size to the other known hyperlipidaemia precipitants, and has a greater effect in males. The protective effect of APOE2/2 genotype for prevalent CVD is consistent with the intrinsically lower apoB concentration.