Risk factors for the presence and development of Familial Dysbetalipoproteinemia in subjects from the general population with an APOE2E2 genotype
Authors: Heidemann B.E , Wolters F.J , Kavousi M , Gruppen E.G , Dullaart R.P.F , Visseren F.L.J , Koopal C 
Published: November 2020

Abstract

Background
Subjects who carry one or two ɛ2 alleles of the APOE gene are protected from cardiovascular disease due to low LDL-cholesterol levels. However, 10–18% of ɛ2 homozygotes (ɛ2ɛ2) develop Familial Dysbetalipoproteinemia (FD), which is characterized by extensive remnant lipoprotein accumulation, making it a good model to study the effect of remnants on atherosclerosis and cardiovascular disease. Important causal factors for FD, or an “FD like phenotype” in ɛ2 heterozygotes (ɛ2ɛ3), are thought to be adiposity and insulin resistance. However, to date this relation was only evaluated in cross-sectional studies.

Purpose
To evaluate the cross-sectional and longitudinal association of adiposity and insulin resistance on the presence and development of FD in ɛ2ɛ2 or an “FD-like” phenotype in ɛ2ɛ3 subjects.

Methods
For this study we included 18042 subjects with an APOE measurement from two Dutch population-based cohorts; the PREVEND cohort (follow-up 4.1 (interquartile range (IQR) 4.0–4.4) years) and the Rotterdam Study (follow-up 10.1 (IQR 5.6–10.8) years). Subjects with an ɛ3ɛ3 genotype (n=10391) and ɛ4 carriers were excluded (n=5265). FD and “FD like” phenotype were defined as triglyceride levels &gt;3 mmol/l or use of lipid lowering medication. Logistic regression models were used to evaluate the effect of age, sex, BMI, waist circumference, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) on FD lipid phenotype. Changes in adiposity measures and insulin resistance between baseline and follow-up were compared in subjects with and without development of FD at follow-up.

Results
In total, 2386 subjects were included of whom 118 participants had ɛ2ɛ2 and 2268 had ɛ2ɛ3 of whom 68% completed a follow-up visit. Subjects mean age was 59±14 years and 44% were male. In ɛ2ɛ2 subjects, 19% (n=23) had FD at baseline and 16% (n=11) developed FD during follow-up. In ɛ2ɛ3 subjects 13% (n=305) had an “FD like” phenotype at baseline and 11% (n=146) at follow-up. Cross-sectional determinants for the presence of an FD or “FD like” phenotype at baseline were male sex, BMI, waist circumference and non-lipid MetS criteria.
In ɛ2ɛ2 subjects who developed FD during follow-up, markers of adiposity and insulin resistance did not change compared to baseline. However, these FD patients more often had adiposity (BMI, weight and waist circumference) and T2DM at baseline, compared to those and who did not developed FD.

Conclusions
These results show for the first time that adiposity and insulin resistance are important risk markers for future development of FD or “FD like” phenotype in ɛ2ɛ2- and ɛ2ɛ3 subjects. The increased susceptibility of ɛ2 carriers for development of an FD lipid phenotype by adiposity and insulin resistance might be due to impaired remnant clearance consequent to decreased binding affinity of APOɛ2 to the LDL-receptor in combination with degradation of the heparan sulfate receptor by insulin resistance (mediated by sulfatase 2 activation).
Odds Ratios for FD lipid phenotype

Funding Acknowledgement
Type of funding source: Public hospital(s). Main funding source(s): UMC Utrecht; Erasmus MC; UMC Groningen