Garcia-Calzon, S. (Sonia)
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- Sex differences in the methylome and transcriptome of the human liver and circulating HDL-cholesterol levels(Oxford University Press, 2018) Perfilyev, A. (Alexander); Ling, C. (Charlotte); Garcia-Calzon, S. (Sonia); Mello, V.D. (Vanessa D.) de; Pihlajamäki, J. (Jussi)Context: Epigenetics may contribute to sex-specific differences in human liver metabolism. Objective: To study the impact of sex on DNA methylation and gene expression in human liver. Design/setting: Cross-sectional, Kuopio Obesity Surgery Study. Participants/intervention: We analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)-cholesterol levels compared with males. Gene expression was measured with the HumanHT-12 Expression BeadChip in a subset of 42 participants. Results: Females displayed higher average methylation in the X-chromosome, whereas males presented higher methylation in autosomes. We found 9455 CpG sites in the X-chromosome and 33,205 sites in autosomes with significant methylation differences in liver between sexes (q < 0.05). When comparing our findings with published studies, 95% of the sex-specific differences in liver methylation in the X-chromosome were also found in pancreatic islets and brain, and 26 autosomal sites showed sex-specific methylation differences in the liver as well as in other human tissues. Furthermore, this sex-specific methylation profile in liver was associated with hepatic gene expression changes between males and females. Notably, females showed higher HDL-cholesterol levels, which were associated with higher KDM6A expression and epigenetic differences in human liver. Accordingly, silencing of KDM6A in cultured liver cells reduced HDL-cholesterol levels and APOA1 expression, which is a major component of HDL particles. Conclusions: Human liver has a sex-specific methylation profile in both the X-chromosome and autosomes, which associates with hepatic gene expression changes and HDL-cholesterol. We identified KDM6A as a novel target that regulates HDL-cholesterol levels.
- The Pro12Ala polymorphism of the PPARγ2 gene interacts with a Mediterranean Diet to prevent telomere shortening in the PREDIMED-NAVARRA randomized trial(American Heart Association, 2014) Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Razquin, C. (Cristina); Garcia-Calzon, S. (Sonia); Corella, D. (Dolores); Zalba, G. (Guillermo); Salas-Salvado, J. (Jordi); Marti-del-Moral, A. (Amelia)Background: The gene variant Pro/Ala (rs1801282) in the PPARγ2 has been associated with lower cardiovascular risk and greater benefit from lifestyle interventions. This polymorphism also seems to be associated with longer lifespan, but no information on telomere length (TL) is available. Our aim was to study the association between the Ala allele and changes in TL in high cardiovascular risk subjects, and the potential interaction with a Mediterranean Diet (MeDiet) pattern. Methods and Results: A total of 521 subjects (55-80 years) participating in the Prevención con Dieta Mediterránea (PREDIMED) randomized trial were genotyped. Changes in TL, measured by quantitative real-time PCR, were assessed over 5 years of a nutritional intervention which promoted adherence to the MeDiet. Interestingly, Ala carriers showed lower telomere shortening after 5 years, compared with the Pro/Pro genotype (P=0.031). This association was modulated by MeDiet since those Ala carriers who reported better conformity to the MeDiet exhibited increased TL (P<0.001). Moreover, a reduction in carbohydrate intake (≤9.5 g/d) resulted in increased TL among Ala carriers. Notably, an apparent gene-diet interaction was found through the observed changes in the MUFA+PUFA/Carbohydrates ratio: as this ratio increased, TL lengthening was detected to a greater extent in the Ala carriers compared with the Pro/Pro subjects (P for interaction <0.001). Conclusions: The Pro12Ala polymorphism is associated with TL homeostasis after 5 years follow-up in subjects at high cardiovascular risk. In addition, a higher adherence to the MeDiet
- Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population(Elsevier, 2014) Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Moleres, A. (Adriana); Garcia-Calzon, S. (Sonia); Zalba, G. (Guillermo); Marti-del-Moral, A. (Amelia)Background & Aims: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length. Methods: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6–18 years), who were randomly selected from the GENOI study. Results: A positive correlation between dietary total antioxidant capacity and telomere length (r=0.157, p=0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (β=-0.204, p=0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p=0.023) and 1.37 for white bread (p=0.025). Conclusion: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in S2panish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length.
- Novel subgroups of type 2 diabetes display different epigenetic patterns that associate with future diabetic complications(American Diabetes Association, 2022) Perfilyev, A. (Alexander); Ahlqvist, E. (Emma); Ling, C. (Charlotte); Groop, L. (Leif); Vaag, A. (Allan); Garcia-Calzon, S. (Sonia); Schrader, S. (Silja); Martinell, M. (Mats)Objective: Type 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications. Research design and methods: Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications. Results: We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue. Conclusions: We identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.
- Lifestyle intervention in pregnant women with obesity impacts cord blood DNA methylation, which associates with body composition in the offspring(American Diabetes Association, 2021) Perfilyev, A. (Alexander); Hjort, L. (Line); Ling, C. (Charlotte); Vaag, A. (Allan); Renault, K.M. (Kristina M.); Carlsen, E.M. (Emma Malchau); Garcia-Calzon, S. (Sonia); Nørgaard, K. (Kirsten); Franks, P.W. (Paul W.); Estampador, A.C. (Ángela C.); Jönsson, J. (Josefine); Michaelsen, K.F. (Kim F.); Vendelbo-Lind, M. (Mads)Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR] <5%) when using the Houseman reference-free method to correct for cell composition, and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms, including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared with control subjects. Methylation at 17 sites, annotated to, for example, DISC1, GBX2, HERC2, and HUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR <5%). Moreover, 22 methylation sites were associated with offspring BMI z scores during the first 3 years of life (P < 0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring's lean mass and early growth.
- Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes(American Association for the Advancement of Science, 2020) Maziarz, M. (Marlena); Bacos, K. (Karl); Perfilyev, A. (Alexander); Ahlqvist, E. (Emma); Kalamajski, S. (Sebastian); Ling, C. (Charlotte); Ustinova, M. (Monta); Groop, L. (Leif); Vaag, A. (Allan); Elbere, I. (Ilze); Garcia-Calzon, S. (Sonia); Klovins, J. (Janis); Pihlajamäki, J. (Jussi); Franks, P.W. (Paul W.); Martinell, M. (Mats); Volkov, P. (Petr)Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.
- Decreased cardiotrophin-1 levels are associated with a lower risk of developing the metabolic syndrome in overweight/obese children after a weight loss program(Elsevier, 2013) Martinez, J.A. (José Alfredo); Moreno-Aliaga, M. J. (María Jesús); Azcona-San-Julian, M.C. (María Cristina); Garcia-Calzon, S. (Sonia); Rendo-Urteaga, T. (Tara); Bustos, M. (Matilde); Chueca, M. (María); Oyarzabal, M. (M.); Martinez-Anso, E. (Eduardo); Marti-del-Moral, A. (Amelia)Objective: Cardiotrophin-1 (CT-1) shares some similarities with other cytokines, and participates in the control of energy metabolism. Higher circulating levels are observed in obese humans, but little information is gathered in weight loss (WL) programs. Therefore, we aimed to investigate the association of serum CT-1 levels with metabolic variables and the risk of developing metabolic syndrome (MetS) after a WL program in overweight/obese children. Subjects and Methods: Forty-four overweight/obese children (mean age 11.5 yr; 50% males) undergoing a 10-week WL program were enrolled. Subjects were dichotomized at the median of Body Mass Index-Standard Deviation Score (BMI-SDS) change, as high and low responders after intervention. Results: CT-1 levels were significantly reduced (-48 fmol/mL, p=0.043) in the high responder group after the WL program. They had significantly lower body weight (-3.7 kg, p<0.001), body fat mass (-8%, p<0.001), BMI-SDS (-0.78, p<0.001) and waist circumference (-5.4 cm, p<0.001), and a significant improvement in lipid and glucose profiles (p<0.05). Interestingly, decreased CT-1 levels significantly predicted changes in total cholesterol (41%) and LDL-cholesterol (28%). Moreover, in our participants the lower the CT-1 levels, the higher the reduction in MetS risk components, after the 10- week intervention, (p-ANCOVA=0.040, p-trend=0.024). Conclusion: We showed, for the first time, a reduction in serum CT-1 levels after a WL program and this decrease in CT-1 was strongly associated with a reduction in cholesterol levels and in MetS risk factors in overweight/obese children. Our findings may suggest that CT-1 could be an indirect marker for the diagnosis of MetS in this population.
- Telomere length as a biomarker for adiposity changes after a multidisciplinary intervention in overweight/obese adolescents: the EVASYON study(Public Library of Science, 2014) Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Campoy, C. (Cristina); Marcos, A. (Ascensión); Moleres, A. (Adriana); Azcona-San-Julian, M.C. (María Cristina); Garcia-Calzon, S. (Sonia); Moreno, L.A. (Luis A.); Zalba, G. (Guillermo); Marti-del-Moral, A. (Amelia)CONTEXT: Telomeres are biomarkers of biological aging. Shorter telomeres have been associated with increased adiposity in adults. However, this relationship remains unclear in children and adolescents. OBJECTIVE: To evaluate the association between telomere length (TL) and adiposity markers in overweight/obese adolescents after an intensive program. We hypothesize that greater TL at baseline would predict a better response to a weight loss treatment. DESIGN SETTING PATIENTS AND INTERVENTION: The EVASYON is a multidisciplinary treatment program for adolescents with overweight and obesity that is aimed at applying the intervention to all possibly involved areas of the individual, such as dietary habits, physical activity and cognitive and psychological profiles. Seventy-four participants (36 males, 38 females, 12-16 yr) were enrolled in the intervention program: 2 months of an energy-restricted diet and a follow-up period (6 months). MAIN OUTCOME: TL was measured by quantitative real-time polymerase chain reaction at baseline and after 2 months; meanwhile, anthropometric variables were also assessed after 6 months of follow-up. RESULTS: TL lengthened in participants during the intensive period (+1.9±1.0, p<0.001) being greater in overweight/obese adolescents with the shortest telomeres at baseline (r = -0.962, p<0.001). Multivariable linear regression analysis showed that higher baseline TL significantly predicted a higher decrease in body weight (B = -1.53, p = 0.005; B = -2.25, p = 0.047) and in standard deviation score for body mass index (BMI-SDS) (B = -0.22, p = 0.010; B = -0.47, p = 0.005) after the intensive and extensive period treatment respectively, in boys. CONCLUSION: Our study shows that a weight loss intervention is accompanied by a significant increase in TL in overweight/obese adolescents. Moreover, we suggest that initial longer TL could be a potential predictor for a better weight loss response.
- Mediterranean diet and telomere length in high cardiovascular risk subjects from the PREDIMED-NAVARRA study(Elsevier, 2016-12) Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Lapetra, J. (José); Razquin, C. (Cristina); Garcia-Calzon, S. (Sonia); Zalba, G. (Guillermo); Aros, F. (Fernando); Marti-del-Moral, A. (Amelia)Summary Background & aims A healthy lifestyle has been associated with longer telomeres, but whether Mediterranean Diet (MeDiet) affect telomere length (TL) has not been fully elucidated yet. Our aim was to assess the relationship between MeDiet and TL in high cardiovascular risk subjects in the context of a randomized nutritional intervention trial. Methods We assessed 520 participants (55–80 years, 55% women) from the PREDIMED-NAVARRA trial. Leukocyte TL was measured by qPCR at baseline and after 5 years of a dietary intervention program where subjects were randomly assigned to a low-fat control diet or to two MeDiets, one supplemented with extra virgin olive oil (MeDiet-EVOO) and the other with mixed nuts (MeDiet-nuts). A validated 14-item questionnaire was used to appraise baseline adherence of participants to the MeDiet. Results Better adherence to MeDiet (as appraised by the 14-item score) was associated with longer basal telomeres in women in the baseline cross-sectional analysis, whereas the opposite was observed in men (P interaction = 0.036). Female subjects who scored 10 points had longer basal telomeres (0.27, 95% CI: 0.03–0.52) than women scoring ≤6 points at the beginning of the study (−0.46, 95% CI: −0.85 to −0.7) (P = 0.003). However, allocation to the MeDiet-nuts group (−0.24, 95% CI: −0.38 to −0.01) was associated with a higher risk of telomere shortening after 5 years of intervention, whereas no differences were found for the MeDiet-EVOO group (0.14, 95% CI: 0.02–0.27), in comparison with the Control group (0.07, 95% CI: −0.08 to 0.23) (P = 0.003 and P = 0.537, respectively). Conclusion A greater baseline adherence to a Mediterranean dietary pattern was associated with longer telomeres only in women. No beneficial effect of the intervention with the MeDiet for the prevention of telomere shortening in comparison with a low-fat diet was observed.
- DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes(Elsevier, 2023) Perfilyev, A. (Alexander); Ahlqvist, E. (Emma); Ling, C. (Charlotte); Garcia-Calzon, S. (Sonia); Schrader, S. (Silja); Martinell, M. (Mats)Aims: Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newlydiagnosed individuals with type 2 diabetes. Methods and Results: We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for ~ 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin’s effects on HbA1c. Conclusion: Metformin-associated alterations in DNA methylation partially mediates metformin’s antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes.