Relationship between renal capacity to reabsorb glucose and renal status in patients with diabetes.

AIMS: Interindividual variability in capacity to reabsorb glucose at the proximal renal tubule could contribute to risk of diabetic kidney disease. Our present study investigated, in patients with diabetes, the association between fractional reabsorption of glucose (FRGLU) and degree of renal disease as assessed by urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR). METHODS: FRGLU [1-(glucose clearance/creatinine clearance)] was assessed in 637 diabetes patients attending our tertiary referral centre, looking for correlations between FRGLU and UAE (normo-, micro-, macro-albuminuria) and Kidney Disease: Improving Global Outcomes (KDIGO) eGFR categories: >90 (G1); 90-60 (G2); 59-30 (G3); and<30-16 (G4) mL/min/1.73 m2. Patients were stratified by admission fasting plasma glucose (FPG) into three groups: low (<6mmol/L); intermediate (6-11mmol/L); and high (>11mmol/L). RESULTS: Median (interquartile range, IQR) FRGLU levels were blood glucose-dependent: 99.90% (0.05) for low (n=106); 99.90% (0.41) for intermediate (n=288); and 96.36% (12.57) for high (n=243) blood glucose categories (P<0.0001). Also, FRGLU increased with renal disease severity in patients in the high FPG group: normoalbuminuria, 93.50% (17.74) (n=135); microalbuminuria, 96.56% (5.94) (n=77); macroalbuminuria, 99.12% (5.44) (n=31; P<0.001); eGFR G1, 94.13% (16.24) (n=111); G2, 96.35% (11.94) (n=72); G3 98.88% (7.59) (n=46); and G4, 99.11% (2.20) (n=14; P<0.01). On multiple regression analyses, FRGLU remained significantly and independently associated with UAE and eGFR in patients in the high blood glucose group. CONCLUSION: High glucose reabsorption capacity in renal proximal tubules is associated with high UAE and low eGFR in patients with diabetes and blood glucose levels>11mmol/L.

Dairy consumption is associated with lower plasma dihydroceramides in women from the D.E.S.I.R. cohort.

AIM: In the D.E.S.I.R. cohort, higher consumption of dairy products was associated with lower incidence of hyperglycaemia, and dihydroceramide concentrations were higher in those who progressed to diabetes. Our aim here was to study the relationships between dairy consumption and concentrations of dihydroceramides and ceramides. METHODS: In the D.E.S.I.R. cohort, men and women aged 30-65 years, volunteers from West-Central France, were included in a 9-year follow-up with examinations every 3 years, including food-frequency questionnaires. Two items concerned dairy products (cheese, other dairy products except cheese). At each examination, dihydroceramides and ceramides were determined by mass spectrometry in a cohort subset; in the present study, the 105 people who did not progress to type 2 diabetes were analyzed, as the disorder per se might be a confounding factor. RESULTS: Higher consumption of dairy products (except cheese) was associated with total plasma dihydroceramides during the follow-up, but only in women (P=0.01 for gender interaction). In fact, dihydroceramide levels were lower in women with high vs low consumption (P=0.03), and were significantly increased during follow-up (P=0.01) in low consumers only. There was also a trend for lower ceramides in women with high dairy (except cheese) intakes (P=0.08). Cheese was associated with dihydroceramide and ceramide changes during follow-up (P=0.04 for both), but no clear trend was evident in either low or high consumers. CONCLUSION: These results show that, in women, there is an inverse association between fresh dairy product consumption and predictive markers (dihydroceramides) of type 2 diabetes.

T-cadherin gene variants are associated with type 2 diabetes and the Fatty Liver Index in the French population.

AIM: Adiponectin is an adipocyte-secreted protein associated with insulin sensitivity. T-cadherin is a receptor for high and medium molecular weight adiponectin. In GWAS, T-cadherin gene (CDH13) polymorphisms are associated with circulating adiponectin levels. This study investigated the associations between genetic variants of CDH13 and type 2 diabetes (T2D), and its related parameters, in a Caucasian population. METHODS: Two polymorphisms of CDH13 (rs11646213 and rs3865188) were genotyped in two French cohorts, a general population from the D.E.S.I.R. study (n=5212) and people with T2D in the DIABHYCAR study (n=3123). Baseline adiponectin levels were measured in D.E.S.I.R. participants who were normoglycaemic at baseline, but hyperglycaemic after 3 years (n=230), and in controls who remained normoglycaemic (n=226) throughout. RESULTS: In a cross-sectional analysis, CDH13 genotype distributions differed between those with and without T2D, with T2D odds ratios (OR) of 1.11 (95% CI: 1.04-1.18; P=0.001) and 0.92 (95% CI: 0.87-0.98; P=0.01) for rs11646213 and rs3865188, respectively. The rs11646213 variant, associated with a higher OR for T2D, was also associated with higher BMI (P=0.03) and HbA1c (P=0.006), and lower plasma adiponectin levels (P=0.03) in the D.E.S.I.R. PARTICIPANTS: Conversely, the rs3865188 variant, associated with a lower OR for T2D, was also associated with lower BMI (P=0.03), HbA1c (P=0.02) and Fatty Liver Index (FLI; P≤0.01), and higher plasma adiponectin levels (P=0.002). Associations with HbA1c, FLI and adiponectin levels persisted after adjusting for BMI. CONCLUSION: CDH13 polymorphisms are associated with prevalent T2D in this French population study. The association may be mediated through effects on BMI and/or plasma adiponectin.

Interaction between GPR120 p.R270H loss-of-function variant and dietary fat intake on incident type 2 diabetes risk in the D.E.S.I.R. study.

BACKGROUND AND AIMS: GPR120 (encoded by FFAR4) is a lipid sensor that plays an important role in the control of energy balance. GPR120 is activated by long chain fatty acids (FAs) including omega-3 FAs. In humans, the loss of function p.R270H variant of the gene FFAR4 has been associated with a lower protein activity, an increased risk of obesity and higher fasting plasma glucose levels. The aim of this study was to investigate whether p.R270H interacts with dietary fat intake to modulate the risk of type 2 diabetes (T2D, 198 incident; 368 prevalent cases) and overweight (787 incident and 2891 prevalent cases) in the prospective D.E.S.I.R. study (n = 5,212, 9 years follow-up). METHODS AND RESULTS: The association of p.R270H with dietary fat and total calories was assessed by linear mixed models. The interaction between p.R270H and dietary fat on T2D and overweight was assessed by logistic regression analysis. The p.R270H variant had a minor allele frequency of 1.45% and was not significantly associated with total calories intake, fat intake or the total calories derived from fat (%). However, there was a significant interaction between p.R270H and dietary fat modulating the incidence of T2D (Pinteraction = 0.02) where the H-carriers had a higher risk of T2D than RR homozygotes in the low fat intake category only. The interaction between p.R270H and fat intake modulating the incidence and prevalence of overweight was not significant. CONCLUSION: The p.R270H variant of GPR120 modulates the risk of T2D in interaction with dietary fat intake in the D.E.S.I.R.

Potential risks associated with increased plasma plant-sterol levels.

The consumption of plant sterols is associated with a decrease in LDL cholesterol. However, it is also associated with an increase in plasma plant-sterol (sitosterol, campesterol) levels that may be detrimental. Indeed, the genetic disease sitosterolaemia, which is characterized by elevated plasma levels of plant sterol, is associated with premature atherosclerosis. Yet, although plasma plant-sterol levels are recognized markers of cholesterol absorption, the relationship between such levels and atherosclerosis is not clear. Several studies have analysed the association between plasma plant-sterol levels and cardiovascular disease (CVD), but have found conflicting results. Although the largest prospective trials and genome-wide association studies suggest that high plasma levels of plant sterols are associated with increased CV risk, other studies have reported no such association and even an inverse relationship. Thus, the available data cannot confirm an increased CV risk with plant sterols, but cannot rule it out either. Only a prospective interventional trial to analyse the effects of plant-sterol-enriched food on the occurrence of CV events can exclude a potential CV risk linked with their consumption.

Allelic variations of the vitamin D receptor (VDR) gene are associated with increased risk of coronary artery disease in type 2 diabetics: the DIABHYCAR prospective study.

AIM: Vitamin D deficiency is associated with coronary artery disease (CAD), and the actions of vitamin D are mediated by binding to a specific nuclear vitamin D receptor (VDR). This study investigated the associations of VDR gene variants with CAD in two cohorts of type 2 diabetes patients. METHODS: A cohort of 3137 subjects from the prospective DIABHYCAR study (CAD incidence: 14.8%; follow-up: 4.4 ± 1.3 years) and an independent, hospital-based population of 713 subjects, 32.3% of whom had CAD, were assessed. Three SNPs in the VDR gene were genotyped: rs1544410 (BsmI); rs7975232 (ApaI); and rs731236 (TaqI). RESULTS: In the DIABHYCAR cohort, an association was observed between the A allele of BsmI and incident cases of CAD (HR: 1.16, 95% CI: 1.05-1.29; P = 0.002). Associations were also observed between BsmI (P = 0.01) and TaqI (P = 0.04) alleles and baseline cases of CAD. The AAC haplotype (BsmI/ApaI/TaqI) was significantly associated with an increased CAD prevalence at the end of the study compared with the GCT haplotype (OR: 1.12, 95% CI: 1.02-1.28; P = 0.04). In a cross-sectional study of the independent hospital-based cohort, associations of ApaI (P = 0.009) and TaqI (P = 0.03) alleles with CAD were observed, with similar haplotype results (OR: 1.33, 95% CI: 1.03-1.73; P = 0.03). CONCLUSION: The haplotype comprising the minor allele of BsmI, major allele of ApaI and minor allele of TaqI of VDR (AAC) was associated with an increased risk of CAD in type 2 diabetes patients. This effect was independent of the effects of other known cardiovascular risk factors.

Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study.

CONTEXT: Fat-rich diets are involved in many disorders such as obesity and type 2 diabetes (T2D). The Pro12Ala variant of peroxisome proliferator-activated receptor-γ (PPARγ) is known to modulate body mass index (BMI) and T2D risk. OBJECTIVE: Our aim was to study the interaction effect between PPARγ gene (PPARG) polymorphisms Pro12Ala and 1431C>T and fat intake on incident T2D and BMI in a 9-year prospective cohort drawn from the French general population, the D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study (n=4676). METHODS: Nutritional intake was assessed by a food frequency self-questionnaire completed by each participant. Statistical analyses included logistic regression, analysis of covariance and haplotype analysis, with adjustment for confounding variables. RESULTS: A high fat consumption (the third sex-specific tertile of fat intake, as a percentage of energy intake) was associated with an increased T2D risk among ProPro and CC homozygotes (P(interaction)=0.05, odds ratio (OR) (95% confidence interval (95% CI))=1.73 (1.19-2.52) P=0.004 and OR=1.85 (1.27-2.71) P=0.001, respectively) but not in Ala and T carriers. There was a significant interaction effect between Pro12Ala and 1431C>T on BMI (P(interaction)=0.004); Ala was associated with lower BMI in CC homozygotes and with higher BMI in T carriers while the opposite was found for ProPro. There was also an interaction effect between Pro12Ala and dietary fat intake on BMI (P(interaction)=0.02); AlaAla individuals had a higher BMI than Pro carriers among high fat consumers (27.1 ± 1.0 versus 24.9 ± 0.1 for AlaAla and Pro+, respectively). There was no interaction effect between the 1431C>T single-nucleotide polymorphism and fat intake on BMI. CONCLUSION: Our results indicate strong genetic and nutritional interaction effects on BMI and T2D risk at the PPARG locus in a general population.

Intensifying glycaemic control with insulin reduces adiponectin and its HMW isoform moderately in type 2, but not in type 1, diabetes.

INTRODUCTION: As the impact of diabetes control was not tested on adiponectin (ADPN) levels, this study was designed to assess whether or not controlling hyperglycaemia can affect ADPN. PATIENTS AND METHODS: A total of 15 T1D and 48 T2D patients with HbA(1c) greater than 10% were studied at the time of hospitalization for uncontrolled diabetes. Total, and high-, medium- and low-molecular-weight (HMW, MMW, LMW) ADPN were measured at the time of study inclusion, on days 1 and 8, and at 1, 3 and 6 months after insulin treatment. RESULTS: While diabetes control improved, total and HMW APDN decreased on days 1 and 8, but remained steady thereafter in T2D patients. In T1D patients, ADPN levels remained unchanged throughout the study. CONCLUSION: Glycaemic control with insulin reduces ADPN in T2D patients in the short-term, but was ineffective in T1D.

Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

AIMS/HYPOTHESIS: We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. METHODS: We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. RESULTS: We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. CONCLUSIONS/INTERPRETATION: The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

Sex hormone-binding globulin predicts the incidence of hyperglycemia in women: interactions with adiponectin levels.

OBJECTIVE: Previous evidence has suggested that a low sex hormone-binding globulin (SHBG) concentration is associated with insulin-resistance and a low adiponectin concentration. We investigated the association between SHBG and the risk of hyperglycemia in each sex and we determined potential interactions between SHBG and adiponectin levels in the development of dysglycemia. DESIGN: We used a nested case-control design in the large prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). We studied 227 men and women who were normoglycemic at baseline but hyperglycemic at 3 years (glycemia > or = 6.1 mmol/l or type 2 diabetes). They were matched for sex, age, and body mass index with 227 subjects who remained normoglycemic at 3 years. RESULTS: At baseline, the concentration of SHBG was significantly lower in women who subsequently developed hyperglycemia than in those who remained normoglycemic, with no difference for men. In multiple regression, SHBG at baseline was as an independent determinant of plasma adiponectin levels, in both women (P<0.0001) and men (P=0.002). In multivariate conditional logistic regression taking into account physical activity and changes in waist circumference over the follow-up, plasma SHBG remained significantly associated with the development of hyperglycemia in women but not in men. These associations persisted after adjustment for fasting insulinemia, high fasting glucose, and adiponectin levels. CONCLUSIONS: These findings suggest that a low SHBG level is a strong risk marker for dysglycemia in women, independently of both adiponectinemia and insulinemia. SHBG may therefore improve the identification of women at risk of diabetes.

Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects.

AIMS/HYPOTHESIS: Insulin resistance is related to an increased risk of diabetic retinopathy and nephropathy in type 1 diabetes. Patients with insulin resistance and/or macrovascular disease have abnormally low levels of adiponectin. The aim of this study was to investigate the relationships between adiponectin and renal and retinal diabetic complications in type 1 diabetic patients. METHODS: In this 6-year prospective follow-up observational study, we evaluated the severity of retinopathy at baseline and determined the incident risk of microalbuminuria in 126 normoalbuminuric patients with type 1 diabetes. Each patient was age- and sex-matched to two non-diabetic control subjects. RESULTS: Plasma adiponectin concentrations were significantly higher in diabetic subjects than in control subjects (p < 0.0001). The adiponectin concentration was significantly higher in patients with severe diabetic retinopathy than in those without (39.1+/-14.0 vs 29.0+/-13.0 microg/ml, p = 0.0005). The 18 patients who developed persistent microalbuminuria had higher adiponectin concentrations than the other patients (35.8+/-14.5 vs 30.6+/-13.7 microg/ml). Increased adiponectin concentrations were independently associated with the occurrence of microalbuminuria (p = 0.0158) after adjustment for baseline urinary albumin concentration (p = 0.004), sex (p = 0.0054), blood pressure (NS) and metabolic control (NS). CONCLUSIONS/INTERPRETATION: The elevated adiponectin concentrations observed in subjects with microvascular disease may indicate an altered regulation of this adipocytokine in patients with complications associated with type 1 diabetes.

Apolipoprotein B signal peptide polymorphism and plasma LDL-cholesterol response to low-calorie diet.

OBJECTIVE: To assess the effect of the apolipoprotein B Ins/Del signal peptide. Polymorphism on plasma lipid levels in overweight subjects before and after a low-calorie diet. DESIGN: Diet intervention study (25% reduction in energy intake during 2.5 months) in relation to genetic factors. SUBJECTS: A total of 231 unrelated patients (146 women/85 men) recruited on the basis of body mass index (BMI)> or =25 kg/m(2). MEASUREMENTS: BMI, waist to hip ratio, blood lipids and lipoproteins, at entry and after 2.5 months, determination of apo B Ins/Del genotypes. RESULTS: On spontaneous diet, subjects carrying the Del allele had higher LDL-cholesterol (Del/Del: 3.97+/-0.62 mmol/l; Ins/Del: 3.87+/-1.01 mmol/l; Ins/Ins: 3.61+/-0.88 mmol/l) (P=0.038). When submitted to low-calorie diet, subjects with Del/Del genotypes reduced their LDL-cholesterol (-16.8%) more than subjects with Ins/Del or Ins/Ins (-4.7% and +0.9%, respectively) (P=0.001). CONCLUSION: In overweight or obese people, the response of plasma LDL-cholesterol levels to low-calorie diet is modulated by genetic variation at the apo B locus. Overweight subjects with the Del allele of the apo B signal peptide polymorphism are predisposed to high LDL cholesterol levels but their LDL cholesterol responds well to diet. These results demonstrate the importance of the interaction between genes and nutritional environment in the determination of the lipid levels.

[Polymorphism insertion/deletion of apolipoprotein B gene: effect on lipid levels in obese patients]. / Polymorphisme insertion/délétion du gène de l'apolipoprotéine B: effet sur les concentrations lipidiques chez les sujets obèses.

Apolipoprotein B (apoB) is the major proteic component of LDL, VLDL and chylomicrons. Numerous polymorphisms of the apolipoprotein B gene have been described. Particularly, a polymorphism of insertion/deletion located in the coding part of the signal peptide of apoB, associated with modifications of lipid concentrations and the risk of cardiovascular disease, has been reported in the general population. Since obesity is frequently associated with dyslipidemias, the aim of our study was to assess the effect of the insertion/deletion polymorphism of the apolipoprotein B gene on lipid levels in obese subjects. 234 unrelated caucasian obese subjects (74 men and 160 women, aged 39.3 +/- 10.5, BMI : 32.8 +/- 4.7) were recruited. The insertion/deletion polymorphism was determined by electrophoresis in polyacrylamide gels after PCR amplification. The relative frequencies of the Ins and Del alleles were 0.71 and 0.29 respectively. These frequencies were similar to those found in other Caucasian populations. In the whole population, individuals with the Del/Del genotype had significantly higher total-cholesterol to HDL-cholesterol ratios (p = 0.004), LDL-cholesterol to HDL-cholesterol ratios (p = 0.01) and TG-VLDL levels (p < 0.05). They also showed a tendency for higher triglyceride levels (p = 0.09) and lower HDL-cholesterol, apolipoprotein AI and LpAI levels. The allele deletion results in the absence of three amino acids (Leu-Ala-Leu) in the signal peptide of apo B. In the obese people, these structural changes may have some effect on lipid metabolism and cause variation in serum lipid concentrations.

[Polymorphism of aldose reductase gene and susceptibility to retinopathy and nephropathy in Caucasians with type 1 diabetes]. / Polymorphismes du gène de l'aldose réductase et susceptibilité à la rétinopathie et à la néphropathie chez des caucasiens diabétiques de type 1.

Polymorphisms of the -106 mutation and z - 2 or z + 2 microsatellites (-2.1 kb) of the Aldose Reductase (AR) gene have been associated to microangiopathic complications of the diabetes mellitus. The study aimed to establish a relation between the occurrence and progression of the renal and retinal complications and these polymorphisms. The genotypes were realised in 3 populations: DESIR (n = 369), non-diabetic control subjects from the general French population: GENEDIAB (n = 494), type 1 diabetic patients who are suffering from proliferative retinopathy associated with a variable seriousness nephropathy (absent: n = 157; incipient: n = 104; established: n = 126; advanced: n = 107); SURGENE (n = 310), type 1 diabetic patients whom the renal status is prospectively assessed since 1989 in one single center Angers University Hospital. The genotype of the -106 polymorphism was determined using the Molecular Beacons. For the microsatellites analysis, we used an automatized method (GeneScan Abi Prism 3100). There was a strong linkage disequilibrium between the z - 2 allele and the T allele (chi 2 = 120; p = 0.001). The frequency of the C-106T is similar for the DESIR and GENEDIAB cohorts (chi 2 = 3.32; p = 0.19); the Hardy Weinberg law was verified in this group (chi 2 = 0.001, 0.9; p = 1.5 and 0.5 respectively). The law was not verified for the SURGENE cohort (chi 2 = 4.7; p = 0.03) where the frequency of the TT genotype was significantly more important compared to the DESIR population (chi 2 = 6.4; p = 0.01). The z, z - 2 and z + 2 alleles was more frequent compared with other alleles (n = 909, 830 and 349; 39, 38 and 15%). The frequency of the C-106T and microsatellites genotypes did not parallel the nephropathy staging in the GENEDIAB population (chi 2 = 10.9, 2.7, 2.4; p = NS respectively). In the SURGENE population, the survival without renal events did not differ according C-106T and z - 2 or z + 2 microsatellites genotypes (log-rank: 0.6, 3.9, 0.1; p = NS respectively). At the end of the follow-up, we found an effect of the -106 mutation and of the z - 2 microsatellite on the staging of the retinopathy (chi 2 tendency test = 4.61, 0.12; p = 0.031, 0.02; 6 d.f., respectively). The logistic regression multivariable analysis shows that the retinopathy during the final evaluation is independently explained by several factors: diabetes duration (p < 0.0001; OR 21.756; 95% CI: 7.024-67.389), presence of nephropathy (p < 0.0001; OR: 4.086; 95% CI: 2.094-7.973), and genotype TT (p = 0.011; OR: 0.38; 95% CI: 0.18-0.803). In contrast, age of diabetes onset (p = 0.112; OR: 1.556; 95% CI: 0.9-2.692), median HbA1c (p = 0.164; OR: 1.479; 95% CI: 0.85-2.576) and sex (p = 0.156; OR: 1.495; 95% CI: 0.856-2.612) have no independent effect. In conclusion, the association of these AR genetic variants seems absent about the renal risk and slight about the retinal risk associated to the type 1 diabetes mellitus.

LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women.

BACKGROUND: In humans, a mutation of the leptin receptor gene (LEPR) leads to a rare obese syndrome of mendelian inheritance. However, obesity in humans results from interactions between genes and environment, mainly nutritional factors. Variations at the LEPR locus could be involved in the regulation of body weight. DESIGN: Genetic variations at the LEPR locus were screened in a selection of 30 French overweight subjects by Single Strand Conformation Polymorphism (SSCP) analysis, then an association study between genotypes and obesity phenotypes was performed in 179 French overweight patients recruited from the Nutrition Department of Bichat Hospital in Paris who were prescribed a low calorie diet and in 387 unrelated volunteers (98 overweight, 289 normal weight) drawn from the Stanislas Family Study in Nancy. RESULTS: Two new genetic variants were found: T + 70-->C (exon 1) and Asp (A) 96 Asp (G) (exon 4). In Nancy, the T + 70-->C polymorphism was associated with fat mass adjusted for BMI in women (P = 0.025). The genotype and allele frequencies of the Ser (T) 343 Ser (C) polymorphism (exon 9) were significantly different between normal and overweight women, with the T allele being more frequent in the overweight group (T frequency in Nancy, 0.82; in Nancy + Paris, 0.79) than in the normal weight group (0.69; P = 0.017 vs. Nancy overweight, P = 0.003 vs. Nancy + Paris overweight). In women from Nancy, fat mass adjusted for BMI was significantly associated with this polymorphism (P = 0.01). The overweight women carrying the C allele of this polymorphism lost more weight in response to low calorie diet than the non carriers (P = 0.006). CONCLUSIONS: In women, genetic variations at the LEPR gene level are associated with overweight and fat mass in a cross sectional study and with response to low calorie diet in an intervention study. These results indicate that variations at the leptin receptor locus are associated with common obesity phenotypes and are a part of the polygenic influences on the response to nutritional environment.

Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease.

Coronary atherosclerosis is a major cause of death in industrialized countries. Monocytes, which play a key role in atherosclerosis, migrate into the vessel wall, presumably guided by specific chemoattractant and adhesion molecules. A compelling candidate for this role is the chemokine receptor CX3CR1, which is expressed on monocytes and acts as either a chemotactic receptor or an adhesion molecule, depending on whether its ligand, fractalkine, is presented free or membrane bound. A common variant of CX3CR1 was recently identified, encoded by the alleles I249 and M280, which form a common I(249)M(280) haplotype. When CX3CR1 genotypes were analyzed in 151 patients with acute coronary syndromes and in 249 healthy controls, CX3CR1 I249 heterozygosity was associated with a markedly reduced risk of acute coronary events, independent of established acquired coronary risk factors (eg, smoking, diabetes). The adjusted odds ratio for this allele was 0.43 (95% confidence interval, 0.26-0.72; P =.001). Consistent with this, functional analysis of peripheral blood mononuclear cells showed that CX3CR1 I249 heterozygosity was associated with a significant decrease in the number of fractalkine binding sites per cell. The results show that CX3CR1 I249 is an independent genetic risk factor for coronary artery disease and that CX3CR1 may be involved in the pathogenesis of atherosclerotic disease. (Blood. 2001;97:1925-1928)

A new T-287C polymorphism in the 5' regulatory region of the tissue factor pathway inhibitor gene. Association study of the T-287C and C-399T polymorphisms with coronary artery disease and plasma TFPI levels.

Tissue factor pathway inhibitor (TFPI) is an important regulator of the extrinsic blood coagulation pathway. We screened the untranslated 5' region of the TFPI gene for polymorphisms and investigated their possible involvement in arterial thrombosis. The allele frequencies of a new polymorphism, located 287 base pairs upstream of the transcription start site (T-287C), and that of the previously described C-399T polymorphism, were similar in cases and controls. In controls, the -287C allele was associated with significantly higher levels of total TFPI antigen, arguing for an effect of this polymorphism on TFPI gene expression. In controls, the C-399T polymorphism did not alter TFPI levels. In the cases, however, decreased total and post-heparin free TFPI levels and increased F1+2 levels were significantly associated with the -399T allele. These findings suggest that the T-287C and C-399T polymorphisms are not associated with an increased risk of coronary heart disease, a result which should be confirmed by a larger study. However, their influence on outcome, or a link with subtypes of acute coronary syndromes, cannot be excluded.

5-HT2A receptor gene polymorphism is associated with food and alcohol intake in obese people.

OBJECTIVE: To test the association between a polymorphism of the 5-HT2A receptor gene, -1438G/A, and energy and nutrients intake, including alcohol. SUBJECTS: Two hundred and seventy six unrelated overweight subjects (180 women, 96 men) were recruited from the Nutrition Department of Bichat Hospital in Paris on the basis of 120% of ideal body weight (body mass index, BMI=33.3+/-4.8 kg/m2). A second overweight sample (31 women, 49 men) was drawn from the Stanislas Family Study, composed of volunteers for a free health examination in Nancy (BMI=29.6+/-3.1 kg/m2). MEASUREMENTS: Energy and nutrients intake were assessed using the diet history method in Paris and the 3-day record method in Nancy. We analyzed the polymorphism by PCR followed by MspI digestion. Statistical differences between genotypes were assessed by using the non-parametric Kruskal-Wallis test. RESULTS: In the whole overweight population, the A allele was associated with lower energy intake 10. 3+/-2.8, 9.9+/-2.8, 9.3+/-2.9 MJ/day for GG, GA and AA genotypes respectively (P<0.05). This association was significant in the patient sample from Paris and in the overweight male volunteers from Nancy. Allele A-related lowering in energy intake was due to a trend to lower intakes in all the main nutrients. The A allele was also associated with a lower alcohol consumption: 18.4+/-19.7, 15.3+/-21. 2 and 12.3+/-17.5 g/day for GG, GA and AA genotypes, respectively (P<0.05). CONCLUSIONS: These data indicate that a gene polymorphism may influence food and alcohol intake in overweight humans. This could be explained by the role of the serotonergic system as a determinant of food intake.

Beneficial effects of a moderate consumption of red wine on cellular cholesterol efflux in young men.

BACKGROUND AND AIM: Protection against coronary artery disease (CAD) by moderate alcohol consumption is thought to be partly mediated through an increase in high density lipoprotein (HDL) levels. The protective effect of HDL can be related to its role in reverse cholesterol transport. Some studies have shown that wine intake is associated with a lower CAD risk compared to other alcoholic beverages. METHODS AND RESULTS: In order to separate the possible beneficial effects of the alcoholic and the non-alcoholic components of red wine, three beverages were compared in a group of 56 healthy young men: red wine (W) (30 g alcohol/day), a solution with the same degree of alcohol (A) and alcohol-free red wine (AFW). Beverages were consumed in random order over a period of 14 days. W significantly increased serum HDL-C, Apo A-I, HDL3-C, LpA-I and LpA-I:A-II particles. With A, only ApoA-I, HDL3-C, LpA-I:A-II were increased, though triglycerides were also increased. AFW had no effect apart from decreasing HDL-C. Plasma CETP was never altered. Serum-promoted cellular cholesterol efflux was measured on 3H labelled Fu5AH cells. Fractional cholesterol efflux was increased only after W intake, by 7%. Efflux variations correlated positively with HDL-C, HDL3-C and HDL-phospholipid variations. CONCLUSIONS: A modest, specific beneficial effect of moderate red wine consumption was demonstrated in comparison to an alcoholic solution. This was due to its effects on lipoproteins and its stimulation of serum ability to induce efflux of cellular cholesterol.