Background: Despite the richness in antioxidants of the Mediterranean diet, to our knowledge, no randomized controlled trials have assessed its effect on in vivo lipoprotein oxidation. Methods: A total of 372 subjects at high cardiovascular risk (210 women and 162 men; age range, 55-80 years), who were recruited into a large, multicenter, randomized, controlled, parallel-group clinical trial (the Prevenció n con Dieta Mediterránea [PREDIMED] Study) directed at testing the efficacy of the traditional Mediterranean diet (TMD) on the primary prevention of coronary heart disease, were assigned to a low-fat diet (n = 121) or one of 2 TMDs (TMDϩvirgin olive oil or TMDϩnuts). The TMD participants received nutritional education and either free virgin olive oil for all the family (1 L/wk) or free nuts (30 g/d). Diets were ad libitum. Changes in oxidative stress markers were evaluated at 3 months. Results: After the 3-month interventions, mean (95% confidence intervals) oxidized low-density lipoprotein (LDL) levels decreased in the TMD ϩ virgin olive oil (−10.6 U/L [−14.2 to −6.1]) and TMDϩnuts (−7.3 U/L [−11.2 to −3.3]) groups, without changes in the low-fat diet group (−2.9 U/L [−7.3 to 1.5]). Change in oxidized LDL levels in the TMDϩ virgin olive oil group reached significance vs that of the low-fat group (P =.02). Malondialdehyde changes in mononuclear cells paralleled those of oxidized LDL. No changes in serum glutathione peroxidase activity were observed.

There are no good genetic markers for incorporating the study of genetic susceptibility to obesity in epidemiological studies. In animal models, the leptin (LEP) and the leptin receptor (LEPR) genes have been shown to be very important in obesity because leptin functions as a negative feedback signal in regulating body-weight through reducing food intake and stimulating energy expenditure. In humans, several polymorphisms in these genes have been described. However, their association with obesity is still very controversial because there are no good case-control studies designed to specifically test this association. Our objective has been to conduct a population-based case-control study to estimate the risk of obesity arising from the -2548G > A and Q223R polymorphisms in the LEP and LEPR genes, respectively. 303 obese cases (101 men and 202 women) and 606 controls (202 men and 404 women) were selected from a Spanish Mediterranean population. Genetic, clinical and life-style characteristics were analyzed. No association was found between the -2548G > A polymorphism and obesity. However, the Q223R variant was significantly associated with obesity in a recessive model, the RR genotype being more prevalent in controls than in obese subjects. The inverse association between the Q223R polymorphism and obesity (OR = 0.62; 95% CI: 0.39-0.99) remained significant even after additional adjustment for education, tobacco smoking, alcohol, physical activity, origin of the obese patient, and the -2548G > A polymorphism in the LEP gene (OR = 0.54; 95% CI: 0.32-0.89). In conclusion, the -2548G > A polymorphism is not a relevant obesity marker in this Mediterranean population, although Q223R does seen to be so.

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

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