APOE genotypes modulate inflammation independently of their effect on lipid metabolism

Authors: CIVEIRA-MARIN, MARIA - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; CENARRO, ANA - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; MARCO-BENEDI, VICTORIA - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; BEA, ANA - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; MATEO-GALLEGO, ROCIO - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; MORENO-FRANCO, BELEN - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LACLAUSTRA, MARTIN - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; CIVEIRA, FERNANDO - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; LAMIQUIZ-MONEO, ITZIAR - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/24/2022
Publication Date: 10/26/2022
Citation: Civeira-Marin, M., Cenarro, A., Marco-Benedi, V., Bea, A.M., Mateo-Gallego, R., Moreno-Franco, B., Ordovas, J.M., Laclaustra, M., Civeira, F., Lamiquiz-Moneo, I. 2022. APOE genotypes modulate inflammation independently of their effect on lipid metabolism. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms232112947.
DOI: https://doi.org/10.3390/ijms232112947

Interpretive Summary: Apolipoprotein E (ApoE) is a protein that helps transport lipids (fats and cholesterol) in the blood. It is recognized by specific cell surface receptors that allow it to deliver lipids to cells for use or storage and to deliver excess lipids to the liver for excretion. The ApoE protein has three genetic forms that are called ApoE2, ApoE3, and ApoE4. ApoE3 is the most common form. People with the APOE form could be predisposed to a significantly elevated level of LDL-C ("bad cholesterol"). In contrast, people with the APOE2 form tend to have lower LDL-C levels but elevated triglycerides. Both forms have been associated with cardiovascular disease (CVD) risk. The impact of APOE forms on inflammation, another CVD risk factor, has been less studied. Our results on a large population of about 8,000 subjects show that inflammation was higher in APOE2 and lower in APOE4 individuals, supporting the notion that the increased CVD risk of APO4 carriers is due to higher levels of the "bad cholesterol," whereas for APOE2 carriers is due to more elevated triglycerides and inflammation. These data could be used for more precise preventive therapies based on the genetics of APOE.

Technical Abstract: The association between APOE genotypes and cardiovascular disease (CVD) is partially mediated by LDL-cholesterol concentration but persists after adjusting for lipid levels and other cardiovascular risk factors. Data from the Aragon Workers Health Study (AWHS) (n = 4159) and the Lipid Unit at the Hospital Universitario Miguel Servet (HUMS) (n = 3705) were used to investigate the relationship between C-reactive protein (CRP) levels and APOE genotype. Lipoprotein particle and GlycA concentrations were analyzed in a subsample from AWHS. APOE genotyping was carried out by the Sanger method in both cohorts. APOE4 carriers had significantly lower levels of CRP than APOE3 carriers. Furthermore, APOE4 carriers had cholesterol-enriched LDL particles compared to APOE2 carriers. APOE4 carriers also had higher concentrations of small, medium, and large LDL particles. CRP levels were not associated with lipoprotein particle number, size, or composition. GlycA levels were not associated with APOE genotypes. However, GlycA levels were significantly associated with the size and the amount of cholesterol contained in HDL, VLDL, and LDL particles. APOE genotype influences CRP concentration regardless of lipid profile. APOE2 carriers showed the highest CRP levels, followed by APOE3 and APOE4. A more atherogenic lipid profile, but not inflammatory markers could partly explain the higher CVD risk observed in APOE4 carriers.