Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study

Sánchez‐Cabo, Fátima; Fuster, Valentín; Silla-Castro, Juan Carlos; González, Gema de Pablo; Lorenzo-Vivas, Erika; Álvarez, Rebeca; Callejas, Sergio; Benguría, Alberto; Gil, Eduardo; Núñez, Estefanía; Oliva, Belén; Mendiguren, José M.; Cortes‐Canteli, Marta; Bueno, Héctor; Andrés, Vicente; Ordovás, José M.; Fernández‐Friera, Leticia; Quesada, Antonio J; García, José Manuel Pérez; Rosselló, Xavier; Vázquez, Jesús; Dopazo, Ana; Fernández‐Ortíz, Antonio; Ibáñez, Borja; Lara‐Pezzi, Enrique

doi:10.1093/eurheartj/ehad361

Cited by 35 publications

(19 citation statements)

References 48 publications

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“…DNA extraction from peripheral blood was performed as previously described. 19 APOE genotyping was performed by real-time PCR. 20 Real-time PCR reactions were loaded into 384 well plates using a Fluent liquid handling platform (Tecan Trading AG, Männedorf, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

“…For methylomics, blood samples were collected, and DNA was extracted and processed as previously reported. 19 Briefly, 1 µg of high-quality DNA was used for methylome analysis at the CEGEN (Madrid, Spain). First, genomic DNA was subjected to bisulfite conversion with the EZ DNA Methylation Kit (Zymo Research).…”

Section: Methodsmentioning

confidence: 99%

“…19 For transcriptomics, peripheral blood samples were collected in PAXgene Blood RNA tubes (Preanalytix), stored at −80 °C after collection, and processed as previously described. 19 Briefly, total RNA was automatically extracted using a QIAsymphony SP liquid handling robot and the QIAsymphony PAXgene blood RNA kit (Qiagen), following the manufacturer´s instructions. RNA quantity and integrity were measured using a NanoQuant Plate (Tecan) and a 2100 Bioanalyzer (RNA6000 Nano LabChip, Agilent), respectively.…”

Section: Omics Data Generationmentioning

confidence: 99%

“…Individuals at moderate CVD risk did not show within-group differences in subclinical atherosclerosis extent across APOE genotypes (P=0. 19). Yet, Normally distributed continuous variables are indicated as mean±SD; non-normal continuous variables as median (interquartile range); and categorical variables as N (%).…”

Section: Cardiovascular Risk Subclinical Atherosclerosis and Apoe Gen...mentioning

confidence: 99%

“…The PESA omics subcohort, for which proteomics, metabolomics, and methylomics analyses were performed, included 480 PESA participants divided into 2 groups: 240 individuals with higher burden of subclinical atherosclerosis (as measured by 2D-VUS) and 240 with lower burden, matched by age (±3 years), sex and traditional CVRFs (diabetes, smoking, dyslipidemia, and hypertension, prioritizing the matching by this order). 19,27 In addition, transcriptomics data from 36 PESA participants were retrieved from a pilot omics study. Furthermore, new transcriptomics data were generated to enrich the omics subcohort with 42 additional individuals with ε2/ε2 (n=9) and ε4/ε4 (n=33) genotypes, and 20 samples were resequenced from previous RNA-seq experiments to account for batch effects.…”

Section: Omics Substudy Designmentioning

confidence: 99%

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

Toribio-Fernández,

Tristão-Pereira,

Carlos Silla-Castro

et al. 2024

Circulation Research

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Background: APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. Methods: 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 APOE -genotyped, and omics data were additionally evaluated. Results: In the PESA study, the frequencies for APOE -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, APOE -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 LDL (low-density lipoprotein)-cholesterol. In turn, APOE -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]; P =0.00043; femorals: 0.60 [0.47–0.78]; P =9.96×10 − 5 ; coronaries: 0.53 [0.39–0.74]; P =0.00013; and increased PESA score: 0.58 [0.48–0.71]; P =3.16×10 − 8 ). This APOE -ε2 atheroprotective effect was mostly independent of the associated lower LDL (low-density lipoprotein)-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]; P =0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44–0.66]; P =4.70×10 − 9 versus 0.90 [0.57–1.43]; P =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. Conclusions: 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. REGISTRATION: URL: https://www.clinicaltrials.gov : NCT01410318.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%