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. 2023 Nov 15;12(11):2004.
doi: 10.3390/antiox12112004.

Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk

Oscar Coltell  1   2 , Eva M Asensio  2   3 , José V Sorlí  2   3 , Carolina Ortega-Azorín  2   3 , Rebeca Fernández-Carrión  2   3 , Eva C Pascual  3 , Rocío Barragán  2   3 , José I González  2   3 , Ramon Estruch  2   4 , Juan F Alzate  5   6 , Alejandro Pérez-Fidalgo  7   8   9 , Olga Portolés  2   3 , Jose M Ordovas  7   10   11 , Dolores Corella  2   3
Affiliations

Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk

Oscar Coltell et al. Antioxidants (Basel). .

Abstract

Biological aging is a relevant risk factor for chronic diseases, and several indicators for measuring this factor have been proposed, with telomere length (TL) among the most studied. Oxidative stress may regulate telomere shortening, which is implicated in the increased risk. Using a novel estimator for TL, we examined whether adherence to the Mediterranean diet (MedDiet), a highly antioxidant-rich dietary pattern, is associated with longer TL. We determined TL using DNA methylation algorithms (DNAmTL) in 414 subjects at high cardiovascular risk from Spain. Adherence to the MedDiet was assessed by a validated score, and genetic variants in candidate genes and at the genome-wide level were analyzed. We observed several significant associations (p < 0.05) between DNAmTL and candidate genes (TERT, TERF2, RTEL1, and DCAF4), contributing to the validity of DNAmTL as a biomarker in this population. Higher adherence to the MedDiet was associated with lower odds of having a shorter TL in the whole sample (OR = 0.93; 95% CI: 0.85-0.99; p = 0.049 after fully multivariate adjustment). Nevertheless, this association was stronger in women than in men. Likewise, in women, we observed a direct association between adherence to the MedDiet score and DNAmTL as a continuous variable (beta = 0.015; SE: 0.005; p = 0.003), indicating that a one-point increase in adherence was related to an average increase of 0.015 ± 0.005 kb in TL. Upon examination of specific dietary items within the global score, we found that fruits, fish, "sofrito", and whole grains exhibited the strongest associations in women. The novel score combining these items was significantly associated in the whole population. In the genome-wide association study (GWAS), we identified ten polymorphisms at the suggestive level of significance (p < 1 × 10-5) for DNAmTL (intergenics, in the IQSEC1, NCAPG2, and ABI3BP genes) and detected some gene-MedDiet modulations on DNAmTL. As this is the first study analyzing the DNAmTL estimator, genetics, and modulation by the MedDiet, more studies are needed to confirm these findings.

Keywords: DNA methylation; GWAS; Mediterranean diet; aging; antioxidants; epigenetics; fruits; genetics; telomere length.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Association between leukocyte telomere length–DNA methylation and chronological age in the whole population (n = 414). Scatter plots with raw values, Pearson correlation coefficient and p-value.
Figure 2
Figure 2
Boxplot of telomere length–DNA methylation adjusted for age (DNAmTLAdjAge) in men and women (n = 414). Raw data of the age-adjusted variable (DNAmTLAdjAge) per sex and the corresponding p-value for the comparison of means between men and women.
Figure 3
Figure 3
Adherence to Mediterranean diet (means ± SE) in subjects with shorter (n = 194) and longer (n = 220) TL. p = 0.031 for difference of means in a model adjusted for sex and age. p = 0.034 for difference of means in a model additionally adjusted for diabetes and BMI. p = 0.044 in the model additionally adjusted for metformin, insulin, lipid-lowering drugs, hypertension medication, systolic blood pressure, education, smoking, and physical activity. Error bars: SE of means.
Figure 4
Figure 4
Telomere length (DNAmTL) depending on the adherence to the 4-MedDietFood score ranging from 0 to 4. Values are adjusted mean ± SE. p < 0.001 for the lineal trend of the 4-MedDietFood score in Models 1, 2 and 3. Error bars: SE of means.
Figure 5
Figure 5
Manhattan plot of the GWAS of leukocyte telomere length–DNA methylation using a gene-based approach (adjusted for sex and age). The red line represents the threshold (−log10(5 × 10−8)). The blue line represents the threshold (−log10(1 × 10−5)).
Figure 6
Figure 6
Zoom plots of the selected top-ranked SNPs for the GWAS of DNAmTL in this population (Table 5). The panel shows the following SNPs: (A) rs9529615 (Chr.: 13; p = 2.33 × 10−7); (B) rs2178528 (Chr.: 7; p = 8.30 × 10−7).
Figure 7
Figure 7
Combined effect of adherence to Mediterranean diet (MedDiet), expressed as categories (low and high), and genetics using a genetic risk score(GRS) of TERT, TERF2, RTEL1 and DCAF4, with the effect allele associated with shorter telomere length on DNAmTL in women. Models adjusted for age, diabetes, and BMI. Error bars: SE of means. The symbol “*” means interaction between MedDiet and GRS.
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