Nikos Yiannakouris

Association of the +45T>G and +276G>T polymorphisms in the adiponectin gene with insulin resistance in nondiabetic Greek women

OBJECTIVE We explored potential associations of two single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ; +45T>G, rs2241766 and +276G>T, rs1501299) with circulating total and high-molecular weight (HMW) adiponectin, insulin resistance (IR), and markers of obesity in a healthy Greek female population. DESIGN AND METHODS The two SNPs were genotyped in 349 women without diabetes (mean age: 47.0+/-12.1 years, mean body mass index: 28.9+/-5.6 kg/m(2)). Total and HMW adiponectin concentrations, body composition variables, IR parameters, and plasma lipid levels were determined. RESULTS In single SNP analysis adjusting for several potential confounders, SNP +276G>T was associated with higher fasting insulin levels (P=0.01) and higher homeostasis model assessment index for IR (HOMA-IR; P=0.009), and SNP +45T>G was associated with lower insulin levels and HOMA-IR (P=0.05 and P=0.07 respectively). No association with total or HMW adiponectin, plasma lipid levels, and body composition variables was observed; however, haplotype analysis revealed that subjects homozygous for the most common +45T/+276G haplotype had lower total adiponectin levels than did noncarriers of this haplotype (P=0.02). The observed differences in HOMA-IR were very significant among women with a higher body fat (BF) percentage (>or= the population median of 41%; all P<or=0.005), but not among leaner individuals (P for interactions 0.01-0.07), thus suggesting that ADIPOQ effects on insulin sensitivity may depend upon BF status. CONCLUSION Our data suggest a significant role of ADIPOQ variants at positions +45 and +276 in the development of IR in healthy Greek women possibly through an interaction with BF.

Association of Eating Frequency with Body Fatness in Pre‐ and Postmenopausal Women

Objective: To examine associations between eating frequency (EF) and body fatness in pre‐ and postmenopausal women, after excluding potential low‐energy reporters.

Association of apolipoprotein E polymorphism with myocardial infarction in Greek patients with coronary artery disease.

Summary Studies in several populations have indicated that genetic variation at the apolipoprotein E (apoE) structural locus influences the risk of coronary artery disease (CAD) and myocardial infarction (MI). This study aimed at investigating whether apoE polymorphism has an allelic and/or genotypic impact on the risk of MI in Greek patients with CAD. We compared apoE gene polymorphism in a group of patients with angiographically confirmed CAD but not MI [CAD/MI (–)-group, n = 143] and a group of age and sex-matched CAD patients who had experienced a non-fatal MI [CAD/MI (+)-group, n = 124]. The patients were also compared with a group of healthy younger individuals (n = 240) with no family history of CAD. The apoE genotype distribution differed significantly between the two groups of CAD patients (p = 0.02). The ϵ2 allele was 5.3-fold less frequent in the CAD/MI (+)-group compared with the CAD/MI (-)-group (1.2% vs. 6.3%, p = 0.01). The frequency of the ϵ2 allele in healthy subjects was 8.1%, which is 6.8-fold higher than in CAD/MI (+)-patients (p = 0.001) and twice as high compared with all CAD patients (p = 0.02). No differences in ϵ4 allele frequencies were observed between CAD/MI (+)- and CAD/MI (–)-patients (10.9% vs. 9.8%), or between patients with CAD and healthy subjects (10.3% vs. 10.2%). In summary, the ϵ4 allele was not found to be associated with an increased risk for CAD or MI. In contrast, a negative association of the ϵ2 allele with MI was observed among Greek patients with CAD.

Association between glucokinase regulatory protein (GCKR) and apolipoprotein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states.

BACKGROUND Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoprotein A5 (APOA5) and glucokinase regulatory protein (GCKR) genes has been associated with fasting plasma triacylglycerol. OBJECTIVE We investigated the combined effects of the GCKR rs780094C-->T, APOA5 -1131T-->C, and APOA5 56C-->G single nucleotide polymorphisms (SNPs) on fasting triacylglycerol in several independent populations and the response to a high-fat meal and fenofibrate interventions. DESIGN We used a cross-sectional design to investigate the association with fasting triacylglycerol in 8 populations from America, Asia, and Europe (n = 7,730 men and women) and 2 intervention studies in US whites (n = 1,061) to examine postprandial triacylglycerol after a high-fat meal and the response to fenofibrate. We defined 3 combined genotype groups: 1) protective (homozygous for the wild-type allele for all 3 SNPs); 2) intermediate (any mixed genotype not included in groups 1 and 3); and 3) risk (carriers of the variant alleles at both genes). RESULTS Subjects within the risk group had significantly higher fasting triacylglycerol and a higher prevalence of hypertriglyceridemia than did subjects in the protective group across all populations. Moreover, subjects in the risk group had a greater postprandial triacylglycerol response to a high-fat meal and greater fenofibrate-induced reduction of fasting triacylglycerol than did the other groups, especially among persons with hypertriglyceridemia. Subjects with the intermediate genotype had intermediate values (P for trend <0.001). CONCLUSIONS SNPs in GCKR and APOA5 have an additive effect on both fasting and postprandial triacylglycerol and contribute to the interindividual variability in response to fenofibrate treatment.

Mediterranean Diet and Diabetes: Prevention and Treatment

The aim of the present review is to examine current scientific knowledge on the association between the Mediterranean diet and diabetes mellitus (mostly type 2 diabetes). A definition of the Mediterranean diet and the tools widely used to evaluate adherence to this traditional diet (Mediterranean diet indices) are briefly presented. The review focuses on epidemiological data linking adherence to the Mediterranean diet with the risk of diabetes development, as well as evidence from interventional studies assessing the effect of the Mediterranean diet on diabetes control and the management of diabetes-related complications. The above mentioned data are explored on the basis of evaluating the Mediterranean diet as a whole dietary pattern, rather than focusing on the effect of its individual components. Possible protective mechanisms of the Mediterranean diet against diabetes are also briefly discussed.

Disordered eating attitudes: An emerging health problem among Mediterranean adolescents

Aim of the present study was to investigate eating attitudes in a group of Mediterranean high school students. One hundred and twenty high school students participated in this survey. The Eating Attitudes Test (EAT-26) was used for evaluating symptoms and attitudes associated with disordered eating. Body composition and dietary intake were also assessed. Using the cut-off point of 20 in the total EAT, 13 females (20.3%) and 4 males (7.3%) exhibited disordered eating behavior. Overweight students had significantly higher scores in the dieting scale than those in the normal BMI range. Percent fat mass was positively related to the total EAT (r=0.326, p<0.001) and the dieting scale (r=0.489, p<0.001). Waist/hip ratio was negatively related to total EAT and its scales. In conclusion, a significant percentage of students in this urban Mediterranean adolescent population found to have abnormal eating attitudes. This finding may be partly explained by the effect of cultural transition.

Genetic predisposition, nongenetic risk factors, and coronary infarct.

BACKGROUND Using a genetic predisposition score (GPS), additively integrating the associations of 11 polymorphisms with coronary heart disease (CHD), we examined the consequences of the joint presence of a high GPS and nongenetic CHD risk factors. METHODS Within the European Prospective Investigation Into Cancer and Nutrition, 202 case patients with medically confirmed incident coronary infarct and 197 control subjects were identified in Greece. Each polymorphism contributed 1 unit (high-risk homozygous), one-half unit (heterozygous), or no units (low-risk homozygous) to the GPS. Odds ratios of coronary infarction for those at high risk because of genetic predisposition and simultaneous presence of an established CHD risk factor were estimated, compared with subjects at low risk, for both GPS and each CHD risk factor. RESULTS The joint presence of a high GPS (> or =3.5) and each studied CHD risk factor was in all instances associated with a significantly increased risk of coronary infarction. The odds ratio (95% confidence interval) was 2.62 (1.14-6.02) for ever smoking, 2.88 (1.33-6.24) for hypertension, 3.50 (1.67-7.33) for low high-density lipoprotein (HDL) level, 3.05 (1.53-6.08) for high non-HDL level, and 3.66 (1.75-7.65) for poor adherence to the Mediterranean diet. The odds ratios were always lower and nonsignificant when the GPS was low. There was suggestive evidence for interaction of a high GPS with hypertension (P = .05) and non-HDL cholesterol level (P = .13). CONCLUSIONS Genetic predisposition may interact with hypertension and, perhaps, also with the level of non-HDL cholesterol, in the causation of CHD. Genetic predisposition and the other studied exposures seem to have converging effects. Thus, the GPS may identify individuals who could realize disproportional benefits by controlling their hypertension and, possibly, their non-HDL cholesterol level.

Apolipoprotein E Genotype in Dyslipidemic Patients and Response of Blood Lipids and Inflammatory Markers to Alpha-Linolenic Acid

The objective of this study was to determine the effect of alpha-linolenic acid (ALA) supplementation on blood lipids and inflammatory markers, in relation to apolipoprotein (apo) E genotype. The diets of 50 dyslipidemic male patients were supplemented with 15 mL of flaxseed oil per day for 12 weeks. Retrospectively, 3 apo E genotype variants were found (ε2/ε3, n=7; ε3/ε3, n=33; ε3/ε4, n=10). No significant differences were found among apo E genotypes in any variables at baseline. ALA supplementation produced a small but significant decrease in high-density lipoprotein cholesterol (from 1.12 to 1.08 mmol/L, 43 to 42 mg/dL; p=0.008) and apo A-I levels (from 1.28 to 1.24 g/L, p=0.036) in the ε3/ε3 homozygotes. In addition, ALA supplementation resulted in a significant decrease in the serum concentration of serum amyloid A (SAA) (p=0.014), C-reactive protein (CRP) (p=0.013), macrophage colony-stimulating factor (MCSF) (p<0.001), and interleukin (IL)-6 (p=0.028). Serum SAA and MCSF were also significantly decreased in the ε3/ε4 group (p=0.005 and p=0.017, respectively). In contrast, ALA produced no effects on any of the inflammatory markers in the ε2/ε3 group. ALA may have beneficial effects on inflammation in dyslipidemic carriers of the apo ε3/ε3 and ε3/ε4 genotypes, but not in carriers of the ε2 allele.

Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study.

MicroRNAs (miRNAs) are post‐transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single‐nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log‐additive model. Furthermore, several of these miRNAs passed the gene‐based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR‐29a/miR‐29b‐1 cluster were associated with diffuse subtype (minimum p‐value = 1.7 × 10−4; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30–2.28), two tagSNPs of the miR‐25/miR‐93/miR‐106b cluster were associated with cardia GC (minimum p‐value = 5.38 × 10−3; OR = 0.56, 95% CI = 0.37–0.86) and one tagSNP of the miR‐363/miR‐92a‐2/miR‐19b‐2/miR‐20b/miR‐18b/miR‐106a cluster was associated with noncardia GC (minimum p‐value = 5.40 × 10−3; OR = 1.41, 95% CI = 1.12–1.78). Some functionally validated target genes of these miRNAs are implicated in cancer‐related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.

The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender

Objective:To explore the influence of gender, together with folate status, on the relation between the common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children.Design:Cross-sectional study by face-to-face interview.Setting and subjects:A total of 186 sixth-grade students participated from twelve randomly selected primary schools in Volos, Greece.Methods:Fasting tHcy, folate, and vitamin B12 were measured in plasma. The MTHFR genotypes were determined. Anthropometric and dietary intake data by 24-h recall were collected.Results:Geometric means for plasma tHcy, plasma folate and energy-adjusted dietary folate did not differ between females and males. The homozygous mutant TT genotype was associated with higher tHcy only in children with lower plasma folate concentrations (<19.9 nmol/l, P=0.012). As a significant gender interaction was observed (P=0.050), we stratified the lower plasma folate group by gender and found that the association between the genotype and tHcy was restricted to males (P=0.026). Similar results were obtained when folate status was based on estimated dietary folate. Specifically, only TT males that reported lower dietary folate consumption (<37 μg/MJ/day) had tHcy that was significantly higher than tHcy levels of C-allele carriers (P=0.001).Conclusions:Under conditions of lower folate status (as estimated by either plasma concentration or reported dietary consumption), gender modifies the association of the MTHFR(C677T) polymorphism with tHcy concentrations in healthy children.Sponsorship:Kellog Europe.