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 45 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%

Section: Omics Data Generationmentioning

confidence: 99%

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

confidence: 99%

Section: Omics Substudy Designmentioning

confidence: 99%

See 3 more Smart Citations

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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Gut microbiota and epigenetic age acceleration: a bi-directional Mendelian randomization study

Xu,

Li,

Kim

et al. 2024

Aging Clin Exp Res

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Background The gut microbiota is closely related to aging, but the genetic relationship between gut microbiota and aging has not been well investigated. The aim of the study was to explore the association of microbiota with epigenetic age acceleration (EAA) using the Mendelian randomization. Method The independent genetic instruments of gut microbiota were obtained from MiBioGen consortium and the Dutch Microbiome Project. EAA data were derived from genome-wide association study. To assess the causal relationship between gut microbiota and EAA, we applied four different methods of Mendelian Randomization (MR) analysis: the inverse variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WMA), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. Results We identified potential causal associations between 12 bacterial taxa and EAA (PIVW and PWMA < 0.05). Among them, species Holdemania_unclassified (OR: 1.31, 95% CI: 1.13–1.52, P = 0.0004) retained a strong positive association with GrimAge acceleration. Family Acidaminococcaceae (OR: 0.64, 95% CI: 0.44–0.93, P = 0.019) and family Clostridiaceae1 (OR: 0.69, 95% CI: 0.49–0.97 P = 0.031) were negative association with GrimAge acceleration. Reverse MR analyses indicated that EAA was associated with 6 bacterial taxa in IVW and WMA. Among them, a strong inverse association was found between Phenoage acceleration and genus Turicibacter (OR: 0.928, 95%CI: 0.888–0.971, PIVW and PWMA < 0.001). Conclusion Our study implicates the potential causal effects of specific microbiota on EAA, potentially providing novel insights into the prevention aging through specific gut microbiota.

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Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

Ye,

Wang,

Little

et al. 2024

Acta Pharmaceutica Sinica B

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

Cited by 45 publications

References 48 publications

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

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

Gut microbiota and epigenetic age acceleration: a bi-directional Mendelian randomization study

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

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