Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study.

Abstract

APOE is a known genetic contributor to cardiovascular disease, but the differential role <i>APOE</i> alleles play in subclinical atherosclerosis remains unclear. The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were <i>APOE</i>-genotyped, and omics data were additionally evaluated. In the PESA study, the frequencies for <i>APOE</i> -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, <i>APOE</i>-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, <i>APOE</i>-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47-0.81]; <i>P</i>=0.00043; femorals: 0.60 [0.47-0.78]; <i>P</i>=9.96×10^-5; coronaries: 0.53 [0.39-0.74]; <i>P</i>=0.00013; and increased PESA score: 0.58 [0.48-0.71]; <i>P</i>=3.16×10^-8). This <i>APOE</i>-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50-54 years: 0.49 [95% CI, 0.32-0.73]; <i>P</i>=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44-0.66]; <i>P</i>=4.70×10^-9 versus 0.90 [0.57-1.43]; <i>P</i>=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2's atheroprotective effect. This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. URL: https://www.clinicaltrials.gov: NCT01410318.