Association between type 2 diabetes and depressive symptoms after a 1-year follow-up in an older adult Mediterranean population.

OBJECTIVES: To examine the cross-sectional association between baseline depressive symptoms and the presence of type 2 diabetes (T2D), and its association with glycated hemoglobin (HbA1c) and other metabolic variables, and the prospective association of depressive symptoms and HbA1c after 1 year of follow-up. METHODS: n = 6224 Mediterranean older adults with overweight/obesity and metabolic syndrome (48% females, mean age 64.9 ± 4.9 years) were evaluated in the framework of the PREDIMED-Plus study cohort. Depressive symptoms were assessed using the Beck Depression Inventory-II and HbA1c was used to measure metabolic control. RESULTS: The presence of T2D increased the likelihood of higher levels of depressive symptoms (χ2 = 15.84, p = 0.001). Polynomial contrast revealed a positive linear relationship (χ2 = 13.49, p = 0.001), the higher the depressive symptoms levels, the higher the prevalence of T2D. Longitudinal analyses showed that the higher baseline depressive symptoms levels, the higher the likelihood of being within the HbA1c ≥ 7% at 1-year level (Wald-χ2 = 24.06, df = 3, p < .001, for the full adjusted model). Additionally, depressive levels at baseline and duration of T2D predicted higher HbA1c and body mass index, and lower physical activity and adherence to Mediterranean Diet at 1 year of follow-up. CONCLUSIONS: This study supports an association between T2D and the severity of depressive symptoms, suggesting a worse metabolic control from mild severity levels in the short-medium term, influenced by lifestyle habits related to diabetes care. Screening for depressive symptoms and a multidisciplinary integrative therapeutic approach should be ensured in patients with T2D.

Acilcarnitinas en plasma y riesgo de insuficiencia cardiaca y fibrilación auricular: el estudio Prevención con dieta mediterránea / Plasma acylcarnitines and risk of incident heart failure and atrial fibrillation: the Prevención con dieta mediterránea study

Introducción y objetivos La desregulación del metabolismo de los ácidos grasos en la mitocondria es un mecanismo involucrado en el desarrollo de insuficiencia cardiaca (IC) y fibrilación auricular (FA). Se evaluó la asociación entre la concentración plasmática de acilcarnitinas y la incidencia de IC o FA y si la dieta mediterránea (DietMed) puede atenuar la asociación entre las acilcarnitinas y el riesgo de IC o FA. Métodos Dos estudios de casos y controles anidados en el ensayo Prevención con dieta mediterránea (PREDIMED). Se incluyó a participantes con elevado riesgo cardiovascular en España: 326 casos incidentes de IC y 509 de FA se emparejaron individualmente con 1 a 3 controles. Las acilcarnitinas en plasma se midieron con espectrometría de masas en tándem con cromatografía líquida de alta resolución. Se ajustaron modelos de regresión logística condicional para estimar las OR multivariables y los IC95%. Se evaluaron interacciones multiplicativas y aditivas por el grupo de intervención, obesidad (índice de masa corporal ≥ 30) y diabetes mellitus tipo 2. Resultados Las altas concentraciones de acilcarnitinas de cadena mediana y larga se asociaron con un mayor riesgo de IC (respectivamente, ORporDE ajustada=1,28; IC95%, 1,09-1,51, y ORporDE ajustada=1,21; IC95%, 1,04-1,42). Se observó una asociación significativa entre las acilcarnitinas de cadena larga y el riesgo de FA: 1,20 (1,06-1,36). Se encontró una interacción aditiva entre las acilcarnitinas de cadena larga y la FA con la DietMed suplementada con aceite de oliva virgen extra (p de interacción=0,036) y con la obesidad (p=0,022) de forma inversa y directa respectivamente. Conclusiones En las personas con alto riesgo cardiovascular, las altas concentraciones de acilcarnitinas de cadena larga se asocian con mayor riesgo de IC y FA incidentes. Una intervención con DietMed+aceite de oliva virgen extra puede reducir el riesgo asociado con las acilcarnitinas de cadena larga (AU)

Introduction and objectives Fatty acid metabolic dysregulation in mitochondria is a common mechanism involved in the development of heart failure (HF) and atrial fibrillation (AF). We evaluated the association between plasma acylcarnitine levels and the incidence of HF or AF, and whether the mediterranean diet (MedDiet) may attenuate the association between acylcarnitines and HF or AF risk. Methods Two case-control studies nested within the Prevención con dieta mediterránea (PREDIMED) trial. High cardiovascular risk participants were recruited in Spain: 326 incident HF and 509 AF cases individually matched to 1 to 3 controls. Plasma acylcarnitines were measured with high-throughput liquid chromatography-tandem mass spectrometry. Conditional logistic regression models were fitted to estimate multivariable OR and 95%CI. Additive and multiplicative interactions were assessed by intervention group, obesity (body mass index ≥ 30 kg/m2), and type 2 diabetes. Results Elevated levels of medium- and long-chain acylcarnitines were associated with increased HF risk (adjusted ORperDE, 1.28; 95%CI, 1.09-1.51 and adjusted ORperDE, 1.21; 95%CI, 1.04-1.42, respectively). A significant association was observed for AF risk with long-chain acylcarnitines: 1.20 (1.06-1.36). Additive interaction of the association between long-chain acylcarnitines and AF by the MediDiet supplemented with extra virgin olive oil (P for additive interaction=.036) and by obesity (P=.022) was observed in an inverse and direct manner, respectively. Conclusions Among individuals at high cardiovascular risk, elevated long-chain acylcarnitines were associated with a higher risk of incident HF and AF. An intervention with MedDiet+extra-virgin olive oil may reduce AF risk associated with long-chain acylcarnitines (AU)

Asociación entre salud cardiovascular ideal y longitud telomérica en una población de edad avanzada de la cohorte SUN / Association between ideal cardiovascular health and telomere length in participants older than 55 years old from the SUN cohort

Introducción y objetivos: Los telómeros son regiones no codificantes localizadas al final de los cromosomas de células eucariotas, y su acortamiento se ha visto relacionado con la enfermedad cardiovascular y sus factores de riesgo. El objetivo de este estudio es evaluar la asociación entre el índice de salud cardiovascular ideal y el riesgo de telómero corto en una población de sujetos de edad avanzada de la cohorte Seguimiento Universidad de Navarra (SUN). Métodos: Se valoró a 886 adultos mayores de 55 años (645 varones y 241 mujeres). La longitud telomérica se midió utilizando qPCR (quantitative protein chain reaction) en tiempo real y reacción única. El índice de salud cardiovascular «Life's simple 7» se definió según la American Heart Association mediante la puntuación de 7 ítems con valores de 0 a 2 para cada uno: tabaquismo, actividad física, dieta, índice de masa corporal, presión arterial, colesterol total y glucosa en sangre. La máxima puntuación del índice corresponde a 14 puntos. Se categorizó en terciles: pobre (0-9 puntos), intermedio (10-11 puntos) e ideal (12-14 puntos). El riesgo de telómero corto se definió como una longitud telomérica por debajo del percentil 20. Resultados: Sujetos con altos valores en el índice de salud cardiovascular ideal tenían menos riesgo de telómero corto (OR ajustada=0,60; IC95%, 0,34-1,05; p de tendencia lineal=0,052). Esta asociación fue significativa en varones (OR ajustada=0,37; IC95%, 0,17-0,83; p de tendencia lineal=0,025), pero no en mujeres. Conclusiones: En varones mayores de 55 años, existe una asociación inversa entre el índice de salud cardiovascular y el riesgo de tener telómeros cortos (AU)

Introduction and objectives: Telomeres are noncoding regions located at the end of chromosomes and their shortening has been associated with risk factors and cardiovascular disease. The aim of this study was to evaluate the association between ideal cardiovascular health (Life's simple 7) and the odds of having short telomeres in a subsample of participants older than 55 years from the Seguimiento Universidad de Navarra (SUN) study. Methods: We included 886 participants older than 55 years (645 men and 241 women). Telomere length was measured using a real-time quantitative polymerase chain reaction. Cardiovascular health score was defined by the American Heart Association as a composite score of 7 key risk factors (smoking status, physical activity, diet, body mass index, blood pressure, total cholesterol, and fasting blood glucose) with 0 to 2 points for each factor. We categorized this score in tertiles as poor (0-9 points), intermediate (10-11 points) and ideal (12-14 points). The odds of having short telomeres was defined as telomere length below the 20th percentile. Results: Individuals with higher ideal cardiovascular health had a lower prevalence of having short telomeres (adjusted OR, 0.60; 95%CI, 0.34-1.05; P trend=.052). This association was statistically significant in men (adjusted OR, 0.37; 95%CI, 0.17-0.83; P trend=.025) but not in women. Conclusions: An inverse association between cardiovascular health score and short telomeres was found especially for men older than 55 years in the SUN population (AU)

Exploratory dietary patterns and cognitive function in the "Seguimiento Universidad de Navarra" (SUN) Prospective Cohort.

BACKGROUND: Dementia is projected to affect 135 million by 2050. Diet is a pertinent target for primary prevention, but firm recommendations for dementia prevention are not available yet. Our aim was to address the association between exploratory (empirically derived) dietary patterns (DP) and changes in the Spanish Telephone Interview for Cognitive Status (STICS-m, maximum score = 41 points) over 6 years. METHOD: Information on diet was collected with a validated 136-item food-frequency questionnaire from 803 participants in the Mediterranean cohort "Seguimiento Universidad de Navarra." We used principal component analysis to derive exploratory DP. The derived DP were associated with change in STICS-m scores over 6 years, through adjusted multiple linear regression models. RESULTS: Two main DP were identified. The first DP resembled a Western dietary pattern (WDP)-high in sugar, fat, processed foods, and red meat-and the second DP resembled a Mediterranean dietary pattern (MDP)-high in vegetables, fruits, nuts, fish, and olive oil. Adherence to the WDP (tertile 3 vs tertile 1) was significantly associated with negative STICS-m changes after 6 years (between-tertile difference in changes: -0.80 points; 95% confidence interval [CI] -1.51, -0.08, p value = 0.03). Meanwhile, the MDP showed a positive +0.71 point (95% CI 0.15, 1.26, p value = 0.01) between-tertile difference in changes in the STICS-m score. CONCLUSIONS: A healthy, prudent, MDP was associated with less decline in cognitive function and, thus, could help to lower dementia incidence. Western-type diets were associated with a greater decline in cognitive performance and could increase dementia incidence.

Milk and Dairy Products Intake Is Related to Cognitive Impairment at Baseline in Predimed Plus Trial.

SCOPE: To examine the association between milk and dairy products intake and the prevalence of cognitive decline among Spanish individuals at high cardiovascular risk. METHODS AND RESULTS: Cross-sectional analyses are performed on baseline data from 6744 adults (aged 55-75 years old). Intake of milk and dairy products is estimated using a food frequency questionnaire grouped into quartiles. The risk of developing cognitive impairment is based on the Mini-Mental State Examination (MMSE). A higher prevalence of cognitive decline was found in subjects who consumed more grams. Patients with worse MMSE score (10-24) consumed a mean of 395.14 ± 12.21 g, while patients with better MMSE score (27-30) consumed a mean of 341.23 ± 2.73 g (p < 0.05). Those subjects with the lower milk consumption (<220 g/day) had a higher MMSE score (28.35 ± 0.045). Higher intake of fermented dairy products was observed in participants with a lower MMSE score (OR 1.340, p = 0.003). A positive correlation was found between the consumption of whole milk and the MMSE score (r = 0.066, p < 0.001). CONCLUSIONS: These findings suggest that greater consumption of milk and dairy products could be associated with greater cognitive decline according to MMSE. Conversely, consumption of whole-fat milk could be linked with less cognitive impairment in the cross-sectional study.

Mediterranean dietary pattern is associated with lower incidence of premenopausal breast cancer in the Seguimiento Universidad de Navarra (SUN) Project.

OBJECTIVE: Due to the growing interest in the role of dietary patterns (DPs) on chronic diseases, we assessed the association between a posteriori identified DPs in the Seguimiento Universidad de Navarra (SUN) Project - a prospective cohort study in a Mediterranean country - and breast cancer (BC) risk. DESIGN: DPs were ascertained through a principal component analysis based on 31 predefined food groups. BC cases were initially identified through self-report or, if deceased, from death certificates or by notification by the next kin. Women reporting BC were asked to provide a copy of their medical report and diagnoses for confirmation purposes. We fitted Cox regression models to assess the association between adherence to the identified DPs and BC risk. SETTING: Spanish university graduates. PARTICIPANTS: We included 10 713 young and middle-aged - mainly premenopausal - women. RESULTS: After a median follow-up of 10·3 years, we identified 100 confirmed and 168 probable incident BC cases. We described two major DPs: 'Western dietary pattern' (WDP) and 'Mediterranean dietary pattern' (MDP). A higher adherence to a WDP was associated with an increased risk of overall BC (multivariable-adjusted HR for confirmed BC Q4 v. Q1 1·70; 95 % CI 0·93, 3·12; P for trend = 0·045). Contrarily, adherence to a MDP was inversely associated with premenopausal BC (multivariable-adjusted HR Q4 v. Q1 0·33; 95 % CI 0·12, 0·91). No significant associations were observed for postmenopausal BC. CONCLUSIONS: Whereas a higher adherence to the WDP may increase the risk of BC, a higher adherence to the MDP may decrease the risk of premenopausal BC.

Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells

Epigenetic processes, including DNA methylation, might be modulated by environmental factors such as the diet, which in turn have been associated with the onset of several diseases such as obesity or cardiovascular events. Meanwhile, Mediterranean diet (MedDiet) has demonstrated favourable effects on cardiovascular risk, blood pressure, inflammation and other complications related to excessive adiposity. Some of these effects could be mediated by epigenetic modifications. Therefore, the objective of this study was to investigate whether the adherence to MedDiet is associated with changes in the methylation status from peripheral blood cells. A subset of 36 individuals was selected within the Prevención con Dieta Mediterránea (PREDIMED)-Navarra study, a randomised, controlled, parallel trial with three groups of intervention in high cardiovascular risk volunteers, two with a MedDiet and one low-fat control group. Changes in methylation between baseline and 5 years were studied. DNA methylation arrays were analysed by several robust statistical tests and functional classifications. Eight genes related to inflammation and immunocompetence (EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, PPARGC1B) were finally selected as changes in their methylation levels correlated with adherence to MedDiet and because they presented sensitivity related to a high variability in methylation changes. Additionally, EEF2 methylation levels positively correlated with concentrations of TNF-alfa and CRP. This report is apparently the first showing that adherence to MedDiet is associated with the methylation of the reported genes related to inflammation with a potential regulatory impact

Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells.

Epigenetic processes, including DNA methylation, might be modulated by environmental factors such as the diet, which in turn have been associated with the onset of several diseases such as obesity or cardiovascular events. Meanwhile, Mediterranean diet (MedDiet) has demonstrated favourable effects on cardiovascular risk, blood pressure, inflammation and other complications related to excessive adiposity. Some of these effects could be mediated by epigenetic modifications. Therefore, the objective of this study was to investigate whether the adherence to MedDiet is associated with changes in the methylation status from peripheral blood cells. A subset of 36 individuals was selected within the Prevención con Dieta Mediterránea (PREDIMED)-Navarra study, a randomised, controlled, parallel trial with three groups of intervention in high cardiovascular risk volunteers, two with a MedDiet and one low-fat control group. Changes in methylation between baseline and 5 years were studied. DNA methylation arrays were analysed by several robust statistical tests and functional classifications. Eight genes related to inflammation and immunocompetence (EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, PPARGC1B) were finally selected as changes in their methylation levels correlated with adherence to MedDiet and because they presented sensitivity related to a high variability in methylation changes. Additionally, EEF2 methylation levels positively correlated with concentrations of TNF-α and CRP. This report is apparently the first showing that adherence to MedDiet is associated with the methylation of the reported genes related to inflammation with a potential regulatory impact.

Longitudinal association of telomere length and obesity indices in an intervention study with a Mediterranean diet: the PREDIMED-NAVARRA trial.

BACKGROUND: Telomeres are nucleoprotein structures that protect the ends of eukaryote chromosomes. Shorter telomere length (TL) is associated with some age-related human disorders, but its relationship with obesity or adiposity parameters remains unclear. OBJECTIVE: The aim of this study was to assess the relationship between TL and changes in adiposity indices after a 5-year nutritional intervention. DESIGN AND SUBJECTS: TL was measured by quantitative real-time PCR in 521 subjects (55-80 years, 55% women). Participants were randomly selected from the PREDIMED-NAVARRA centre after they completed a 5-year intervention programme. Anthropometric parameters were directly measured by trained personnel at baseline and on a yearly basis thereafter. TL at baseline and changes in TL after a 5-year intervention were assessed. RESULTS: Higher baseline TL significantly predicted a greater decrease in body weight (B=-1.09 kg, 95% confidence interval (CI): -2.01 to -0.16), body mass index (BMI) (B=-0.47 kg m(-2), 95% CI: -0.83 to -0.11), waist circumference (B=-1.15 cm, 95% CI: -2.28 to -0.01) and waist to height ratio (B=-0.008, 95% CI: -0.010 to -0.001) in multiple-adjusted models. In addition, changes in TL during the 5-year intervention were inversely associated with changes in the four anthropometric variables. The reduction in adiposity indices during the intervention, associated with increasing TL, was even higher among subjects with the longest telomeres at baseline. Logistic regression analysis showed that the risk of remaining obese after 5 years was lower in those participants who initially had the longest telomeres and increased their TL after intervention (odds ratio=0.27, 95% CI: 0.03-2.03). CONCLUSIONS: Our research suggests that TL is inversely associated with changes in obesity parameters. The assessment of TL can provide further insights for biological pathways leading to adiposity. We show for the first time an improvement of obesity indices when an increase in TL is observed after a 5-year Mediterranean diet intervention.

A 3-year Mediterranean-style dietary intervention may modulate the association between adiponectin gene variants and body weight change.

PURPOSE: Adiponectin gene variations have been associated with obesity. There are few interventional studies analyzing this association. The aim of this study was to analyze the effects of a nutritional intervention with Mediterranean-style diet and three (-4034A/C, +45T/G, and +276 G/T) adiponectin gene variants on 3-year body weight changes in high cardiovascular risk patients. SUBJECTS AND METHODS: A total of 737 participants, aged 55-80 at high cardiovascular risk were assigned to a low-fat diet or to a Mediterranean-style diet (MD) groups, one with high intake of virgin olive oil (VOO) and the other with high intake of nuts. Anthropometric parameters were taken at baseline and after 3-year follow-up, and the genotyping of the -4034A/C, +45T/G, and +276 G/T polymorphisms was done. RESULTS: GG genotype of the +45T/G polymorphism was associated with 3-year higher body weight gain (B = 1.399; B = 0.043). TT genotype of the +276G/T polymorphism was linked to the highest 3-year body weight gain in men. Both Mediterranean diets appeared to reverse this effect (p for interaction = 0.053). CONCLUSION: Adiponectin gene variation appeared to be associated with 3-year body weight changes in a high cardiovascular risk population. This association may be modulated by a nutritional intervention with a Mediterranean-style diet.

A 3-year intervention with a Mediterranean diet modified the association between the rs9939609 gene variant in FTO and body weight changes.

INTRODUCTION: The aim of this study was to analyze the effects of the rs9939609 (T/A) gene variant in fat mass and obesity-associated gene (FTO) on body weight changes after 3 years and its modification by a randomized nutritional intervention with a Mediterranean-style diet in a population of subjects at high cardiovascular risk. DESIGN: A substudy of PREDIMED, which is a randomized trial aimed at assessing the effect of the Mediterranean diet (MD) for primary cardiovascular disease prevention. There were three nutritional intervention groups: two of them with a Mediterranean-style diet and the third was a control group advised to follow a conventional low-fat diet. SUBJECTS: A total of 776 high cardiovascular risk subjects aged 55-80 years. MEASUREMENTS: Anthropometric measurements were recorded at baseline and at 3 years. The participants were genotyped by RT-PCR, followed by allelic discrimination. RESULTS: Homozygous subjects had the highest baseline body weight. The dominant model showed that subjects carrying the A allele had the lowest body weight gain (B=-0.685; P=0.022) after 3 years of nutritional intervention compared with nonmutated subjects (TT genotype) regardless of the nutritional intervention. Moreover, this effect was statistically significant in carriers of the A allele only among those allocated to the MD groups (B=-0.830; P=0.018), but it was not significant among those allocated to the control group (P for interaction=0.649). CONCLUSION: This study confirmed the association between body weight and the FTO rs9939609 polymorphism. Interestingly, our results showed that, although at baseline the A allele was associated with higher body weight, after 3 years of nutritional intervention with a Mediterranean-style-diet, A-allele carriers had lower body weight gain than wild type subjects. No interaction between nutritional intervention and the polymorphism was found.

A 3 years follow-up of a Mediterranean diet rich in virgin olive oil is associated with high plasma antioxidant capacity and reduced body weight gain.

BACKGROUND/OBJECTIVES: The aim of this study was to analyze the influence of a Mediterranean dietary pattern on plasma total antioxidant capacity (TAC) after 3 years of intervention and the associations with adiposity indexes in a randomized dietary trial (PREDIMED trial) with high cardiovascular risk patients. SUBJECTS/METHODS: 187 subjects were randomly selected from the PREDIMED-UNAV center after they completed 3-year intervention program. Participants were following a Mediterranean-style diet with high intake of virgin olive oil or high intake of nuts, or a conventional low-fat diet. Adiposity indexes were measured at baseline and at year 3. Plasma TAC was evaluated using a commercially available colorimetric assay kit. RESULTS: Plasma TAC in the control, olive oil and nuts groups was 2.01+/-0.15, 3.51+/-0.14 and 3.02+/-0.14 mM Trolox, respectively after adjusting for age and sex. The differences between the Mediterranean diet and control groups were statistically significant (P<0.001). Moreover higher levels of TAC were significantly associated with a reduction in body weight after 3 years of intervention among subjects allocated to the virgin olive oil group (B=-1.306; 95% CI=-2.439 to -0.173; P=0.025, after adjusting for age, sex and baseline body mass index). CONCLUSIONS: Mediterranean diet, especially rich in virgin olive oil, is associated with higher levels of plasma antioxidant capacity. Plasma TAC is related to a reduction in body weight after 3 years of intervention in a high cardiovascular risk population with a Mediterranean-style diet rich in virgin olive oil.

G allele of the -930A>G polymorphism of the CYBA gene is associated with insulin resistance in obese subjects.

It has been shown that NADPH oxidase plays a role in oxidative stress which has been involved in the development of metabolic syndrome. The -930A/G polymorphism of the CYBA gene (that codes p22phox, a major component of the NADPH oxidase) has been associated with human hypertension and with a reduction in NADPH oxidase activity. In this work, we have examined the influence of the -930A/G polymorphism on obesity risk and insulin resistance in a case-control study of Spanish subjects (n=313). In the obese group (n=159), there was a statistically significant association between the GG genotype of the -930A/G polymorphism of the CYBA gene and fasting insulin levels and HOMA index. This outcome agrees with previous findings concerning functional analyses of this polymorphism and reinforces the hypothesis that insulin resistance is associated with oxidative stress. In conclusion, a protective effect in carriers of the -930A/G polymorphism of the p22phox gene against insulin resistance in a population of Spanish obese adults has been found.

G allele of the –930A>G polymorphism of the CYBA gene is associated with insulin resistance in obese subjects

It has been shown that NADPH oxidase plays a role in oxidative stress which hasbeen involved in the development of metabolic syndrome. The –930A/G polymorphismof the CYBA gene (that codes p22phox, a major component of the NADPHoxidase) has been associated with human hypertension and with a reduction inNADPH oxidase activity. In this work, we have examined the influence of the–930A/G polymorphism on obesity risk and insulin resistance in a case-controlstudy of Spanish subjects (n=313). In the obese group (n=159), there was a statisticallysignificant association between the GG genotype of the –930A/G polymorphismof the CYBA gene and fasting insulin levels and HOMA index. This outcomeagrees with previous findings concerning functional analyses of this polymorphismand reinforces the hypothesis that insulin resistance is associated with oxidativestress. In conclusion, a protective effect in carriers of the –930A/G polymorphism ofthe p22phox gene against insulin resistance in a population of Spanish obese adultshas been found (AU)

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A novel mutation Thr162Arg of the melanocortin 4 receptor gene in a Spanish children and adolescent population.

OBJECTIVE: The melanocortin 4 receptor gene (MC4R) is involved in body weight regulation. While many studies associated MC4R mutations with childhood obesity, information on MC4R mutations in Spanish children and adolescents is lacking. Our objective was to screen a population of children and adolescents from the north of Spain (Navarra) for MC4R mutations and to study the phenotypes of carriers and their families. In addition, functional assays were performed for a novel MC4R mutation. METHODS: The study was composed of 451 Spanish children and adolescents (49% boys), aged 5-18 year. According to the International Obesity Task Force (IOTF) criteria, the groups included 160 obese, 132 overweight and 159 normal-weight control subjects. RESULTS: One novel (Thr162Arg) and three known nonsynonymous mutations in the MC4R gene (Ser30Phe, Thr150Ile, Ala244Glu) were detected heterozygously. The MC4R mutations were found in three male (one obese and two overweight) and two female subjects (one obese and one overweight). The novel mutation did not appear to lead to an impaired receptor function. An unequivocal relationship of MC4R mutations with obesity in pedigrees together with an impaired function of the encoded receptor could not be established for any of the mutations. CONCLUSIONS: The presence of heterozygous MC4R mutations in obese and overweight subjects indicates that these mutations may be a susceptibility factor for obesity development, but lifestyle factors, such as exercise or sedentary activities, may modify their effect.